Acid and alkaline phosphatase activities in a novel phosphorothionate (RPR-11) treated male and female rats. Evidence of dose and time-dependent response

The effect of a novel phosphorothionate, the methyl ester of 2-butenoic acid-3-diethoxy phosphinothioyl (RPR-II) was studied on membrane bound target enzymes Acid (AcP) and Alkaline (AkP) Phosphatases in different tissues of male and female albino Wistar rats. Three sub-chronic doses 0.014 (low), 0.028 (medium) and 0.042 (high)mg/kg-1 were administered to the rats daily for a period of 90 days. The long term and repeated administration of RPR-II caused significant increase of AcP and AkP in serum and kidney (AcP), whereas these enzymes simultaneously decreased significantly in liver, kidney (female rat AkP) and lung tissues in both male and female rats after 45 and 90 days of treatment. However, the kidney AcP increased significantly in both the sexes which is suggestive of an increase in synthesis of this enzyme which may be an adaptive mechanism to the toxicant stress. The changes in serum, liver, kidney and lung of both male and female rats by this compound were statistically significant when compared with two way Anova showing that they are dose and time dependent. The alterations in male rats were statistically insignificant when compared with female rats showing no sexual dimorphism by this compound. Recovery was observed after 28 days of post treatment (withdrawal study) indicating reversal of the toxic symptoms once the toxicant is removed. High degree negative correlation was observed for serum versus liver and lung and in other cases substantial correlation was observed. The changes observed in these enzymes showed that liver was most susceptible followed by lung and kidney. There are marker enzymes and their increase in different tissues might be due to the increased permeability of plasma membrane or cellular necrosis, showing the stress condition of the treated rats. This investigation elucidates the effect of these biomarker enzymes which increased in blood, might be due to the necrosis of liver, kidney and lung tissues by this compound.     

ACID AND ALKALINE PHOSPHATASE ACTIVITIES IN A NOVEL PHOSPHOROTHIONATE (RPR-11) TREATED MALE AND FEMALE RATS. EVIDENCE OF DOSE AND TIME-DEPENDENT RESPONSE

The effect of a novel phosphorothionate, the methyl ester of 2-butenoic acid-3-diethoxy phosphinothioyl (RPR-II) was studied on membrane bound target enzymes Acid (AcP) and Alkaline (AkP) Phosphatases in different tissues of male and female albino Wistar rats. Three sub-chronic doses 0.014 (low), 0.028 (medium) and 0.042 (high) mg/kg-1 were administered to the rats daily for a period of 90 days. The long term and repeated administration of RPR-II caused significant increase of AcP and AkP in serum and kidney (AcP), whereas these enzymes simultaneously decreased significantly in liver, kidney (female rat AkP) and lung tissues in both male and female rats after 45 and 90 days of treatment. However, the kidney AcP increased significantly in both the sexes which is suggestive of an increase in synthesis of this enzyme which may be an adaptive mechanism to the toxicant stress. The changes in serum, liver, kidney and lung of both male and female rats by this compound were statistically significant when compared with two way Anova showing that they are dose and time dependent. The alterations in male rats were statistically insignificant when compared with female rats showing no sexual dimorphism by this compound. Recovery was observed after 28 days of post treatment (withdrawal study) indicating reversal of the toxic symptoms once the toxicant is removed. High degree negative correlation was observed for serum versus liver and lung and in other cases substantial correlation was observed. The changes observed in these enzymes showed that liver was most susceptible followed by lung and kidney. There are marker enzymes and their increase in different tissues might be due to the increased permeability of plasma membrane or cellular necrosis, showing the stress condition of the treated rats. This investigation elucidates the effect of these biomarker enzymes which increased in blood, might be due to the necrosis of liver, kidney and lung tissues by this compound.     

Biochemical changes induced in liver and serum of diplodiatoxin (Stenocarpella maydis) treated male and female rats

Present study was conducted to investigate the acute and sub-acute toxic effect of diplodiatoxin with special reference to biochemical membrane bound enzymes like aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) and RBC acetylcholinesterase (AChE) in male and female rats. For acute study, rats were treated with a single oral dose of 5.7 mg/kg of diplodiatoxin, whereas for sub-acute study, the rats received 0.27 mg/kg/day for 21 days. Acute and sub-acute diplodiatoxin treatment caused loss in body weight and feed intake along with symptoms including irritation, dullness, tremors and convulsions. Diplodiatoxin caused a significant increase in serum ASAT and ALAT and a decrease in activity in the liver in both acute and sub-acute studies. This compound also significantly inhibited RBC AChE. Sexual dimorphism was observed when male rats were compared with female rats (p < 0.05). The enzyme alterations observed in the affected enzymes recovered to the normal levels by day 7 post treatment (withdrawal study) in both acute and sub-acute treated rats. A negative correlation was observed with regard to these enzymes when serum was compared with liver. These enzyme profiles show increases in serum with parallel decrease in liver, indicating necrosis of liver. These results suggest that diplodiatoxin has potential to affect hepatic end-points.     

Biochemical Changes Induced in Liver and Serum of Diplodiatoxin (Stenocarpella maydis) Treated Male and Female Rats

Abstract

Present study was conducted to investigate the acute and sub-acute toxic effect of diplodiatoxin with special reference to biochemical membrane bound enzymes like aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) and RBC acetylcholinesterase (AChE) in male and female rats. For acute study, rats were treated with a single oral dose of 5.7 mg/kg of diplodiatoxin, whereas for sub-acute study, the rats received 0.27 mg/kg/day for 21 days. Acute and sub-acute diplodiatoxin treatment caused loss in body weight and feed intake along with symptoms including irritation, dullness, tremors and convulsions. Diplodiatoxin caused a significant increase in serum ASAT and ALAT and a decrease in activity in the liver in both acute and sub-acute studies. This compound also significantly inhibited RBC AChE. Sexual dimorphism was observed when male rats were compared with female rats (p<0.05). The enzyme alterations observed in the affected enzymes recovered to the normal levels by day 7 post treatment (withdrawal study) in both acute and sub-acute treated rats. A negative correlation was observed with regard to these enzymes when serum was compared with liver. These enzyme profiles show increases in serum with parallel decrease in liver, indicating necrosis of liver. These results suggest that diplodiatoxin has potential to affect hepatic end-points.     

Food flavor cinnamaldehyde-induced biochemical and histological changes in the kidney of male albino wistar rat

Rats were given food flavor cinnamaldehyde (CNMA) orally by gavage at the dose of 2.14, 6.96, 22.62 and 73.5 mg/kg body weight/day for 10, 30 and 90 days. Only the group of rats treated with CNMA at the dose 73.5 mg/kg body weight/day for 90 days showed histological changes in the kidney followed by increased activities of renal, serum and urinary enzymes. CNMA-induced glucosuria in these rats was accompanied by marked proteinuria and creatinuria. Increased serum blood urea nitrogen and serum creatinine and decreased serum protein and glucose levels were observed in these rats. Thus, CNMA at the dose of 73.5 mg/kg body weight/day for 90 days exert its effect on kidney of male albino wistar rat and its effect is time and dose dependent.     

The cytochromes P-450 concentrations in microsomes of liver, kidney and duodenal mucosa of the camel, sheep and goat

The concentration of microsomal cytochromes P-450, and of protein in the homogenate, cytosol and microsomes were measured in the liver, kidney and duodenal mucosa of healthy well-fed male and female camels, sheep and goats. For comparison, data from the liver of male and female rats were also obtained. The protein concentrations in the tissues of adult animals were broadly similar in the four species. The concentration of cytochromes P-450 was highest in the liver, followed by the kidney, then the duodenal mucosa in all the species. No cytochromes P-450 were detected in the tissues of immature (less than 1 mo) male goats, whereas the female goat had the highest concentrations of these enzymes in the liver and kidney when compared with the respective tissues in the other species studied. Males had higher activity of cytochromes P-450 than females in the three tissues, except in the duodenal mucosa of sheep, where males had lower activity than females. In camel liver and sheep kidney, the amount of cytochromes P-450 were similar in the two sexes. The present results suggest that the mature female goat is the species best equipped to handle xenobiotics which are detoxified by the cytochromes P-450 and other drug metabolizing enzymes in diseased or malnourished animals is suggested as these two conditions are known to modify drug metabolizing enzymes.     

Effect of monocrotaline ingestion on liver, kidney, and lung of rats

Young, male rats were administered monocrotaline (MCT) ad libitum in the drinking water (22 μg/ml) for up to 28 days, and the development of toxicity in lung, liver, and kidney was examined. Clearance of perfused 5-hydroxytrytptamine by isolated lungs of treated rats was decreased as early as 14 days. This was accompanied by increases in lung/body weight ratio and in lactate dehydrogenase activity in cell-free bronchopulmonary lavage fluid. Hypertrophy of the right heart and increased inflow perfusion pressure of isolated lungs were apparent by 21 days of MCT treatment. The magnitude of the changes in all of these parameters increased with duration of treatment. After 28 days of treatment biliary indocyanine green excretion was decreased and plasma glutamic pyruvic transaminase activity was slightly elevated. Twenty-eight days of treatment also resulted in elevated blood urea nitrogen, decreased accumulation of p-aminohippuric acid by kidney slices, and increased accumulation of tetraethylammonium by kidney slices. Thus, lung, liver, and kidney are each affected by this MCT treatment regimen, and functional effects on lung precede effects on other tissues.     

Constitutive and induced expression by pyridine and β-naphthoflavone of rat CYP1A is sexually dimorphic

Adult male and female Sprague-Dawley rats were compared in terms of the constitutive levels and inducibility of CYP1A1 and CYP1A2 (CYP1A) in lung, kidney, and liver. CYP1A were induced by i.p. treatment with pyridine (75 mg/kg per day) or β-naphthoflavone (βNF; 25 mg/kg per day) for two consecutive days and analyzed catalytically (via O-dealkylation of resorufin ethers), at the protein level (by Western blot analysis) and at the mRNA level (by Northern blot analysis). In untreated rats, CYP1A1 protein and its mRNA were detectable only in the lung and kidney of females but not males, whereas CYP1A2 protein and its mRNA were detectable only in the liver in either gender. Pyridine treatment upregulated CYP1A1 mRNA and its protein in the lung, kidney and liver in female rats, and upregulated the mRNA but not the protein in the lung and liver in male rats. Conversely, pyridine induced both CYP1A2 mRNA and protein in the liver in female rats, whereas it induced the protein but not its mRNA in the liver in male rats. No gender difference was observed in the plasma elimination rate of administered pyridine. βNF, in contrast to pyridine, induced CYP1A proteins, activities, and mRNA to higher levels in male than in female rats. The results show that the constitutive as well as inducible expression of CYP1A is sexually dimorphic in the Sprague-Dawley rat, with females being more responsive than males to induction by pyridine but with males being more responsive than females to induction by βNF. The findings support the involvement of different mechanisms in CYP1A induction by pyridine and βNF. Received: 20 January 1999 / Accepted: 13 April 1999     

Hormonal regulation of microsomal flavin-containing monooxygenase: tissue-dependent expression and substrate specificity

The substrate- and tissue-dependent hormonal regulation of flavin-containing monooxygenase (EC 1.14.13.8) was studied in male and female rats. Hypophysectomy of males reduced liver microsomal N,N-dimethylaniline N-oxidation, thiobenzamide S-oxidation, and imipramine N-oxidation, although the reduction was not as marked with the latter substrate. Castration also reduced flavin-containing monooxygenase-dependent activities, but not to the same extent as hypophysectomy. Administration of growth hormone or testosterone to hypophysectomized males only partially restored basal activities. In female rats, hypophysectomy had no effect on N,N-dimethylaniline N-oxidation or thiobenzamide S-oxidation and actually stimulated imipramine N-oxidation (98%). These effects were demonstrated to be tissue- and sex-dependent. For example, hypophysectomy markedly (300%) enhanced imipramine N-oxidation in male kidney and significantly decreased the same activity in male and female lung. Correlations between levels of the enzyme determined by immunoquantitation (with antibody to the rat liver enzyme) and activities toward these three substrates, in male and female liver, lung, and kidney, also provide evidence for the existence of multiple forms of flavin-containing monooxygenase, which appear to be under different hormonal regulation.     

Toxicity study of a rubber antioxidant, mixture of 2-mercaptomethylbenzimidazoles, by repeated oral administration to rats.

2-Mercaptobenzimidazole (2-MBI), a rubber antioxidant, is known to exhibit potent antithyroid toxicity in rats and is a candidate as an environmental endocrine disrupter. 2-Mercaptomethylbenzimidazoles (a 1:1 mixture of 4-methyl and 5-methyl isomers, MMBIs), are also employed industrially as rubber antioxidants and are suspected to exert antithyroid toxicity such as 2-MBI. In this investigation, acute and subacute oral toxicity studies of MMBIs in Wistar rats were conducted. The clinical signs of acute oral toxicity were observed including decreased spontaneous movement, a paralytic gait, salivation and lacrimation, and adoption of prone and lateral positions. The LD50 was estimated to be 330 mg/kg. In the subacute oral toxicity study, male and female rats were treated with MMBIs by gavage at doses of 0 (corn oil), 4, 20 and 100 mg/kg for 28 consecutive days followed by a 2-week recovery period for the control and highest dose groups. Body weight and food consumption, clinical signs, organ weights, clinical biochemistry and haematological parameters including clotting times and micronuclei induction in bone marrow erythropoeitic cells, and histopathology were examined. Relative organ weights of lung, liver and kidney, and serum cholesterol and phospholipid significantly increased in male rats treated with MMBIs at doses of 20 and 100 mg/kg. Male rats administered 100 mg/kg MMBIs exhibited a 1.8-fold increase in thyroid weight associated with histopathological changes but not altered serum thyroid hormone levels. Female rats administered 100 mg MMBIs/kg exhibited significant increases of liver and kidney but not thyroid weights, and serum cholesterol level. The antithyroid toxicity of MMBIs in rats was estimated to be one-tenth that of 2-MBI. No-observed-effect levels for male and female rats were found to be 4 and 20 mg/kg, respectively, in this subacute oral toxicity study.     

Toxicity and carcinogenicity of riddelliine in rats and mice

These investigations of riddelliine analyzed potential carcinogenesis and the utility of the female-rat/male-mouse design in bioassays and dose-response. Groups of 50 Fischer rats and B6C3F1 mice were gavage-administered riddelliine 5 days per week for 105 weeks. The dose levels for male rats were 0 or 1.0 mg/kg body weight; female rats 0, 0.01, 0.033, 0.1, 0.33, or 1.0 mg/kg; male mice 0, 0.1, 0.3, or 1.0, 3.0 mg/kg; and female mice 0 or 3.0 mg/kg. The dose groups were purposely designed to evaluate the dose-response relationship only in female rats and male mice. In rats, liver hemangiosarcoma, hepatocellular adenoma, and mononuclear cell leukemia were significantly increased in the 1.0 mg/kg male and female dose groups. Non-neoplastic lesions occurred in the liver and kidney of male and female rats. In mice, hemangiosarcomas increased significantly in the liver of males in the 3.0 mg/kg dose group. Alveolar/bronchiolar neoplasms in the 3.0 mg/kg dose group of female mice were significantly increased. Hepatocellular neoplasms were significantly decreased in the 1.0 mg/kg dose group of male and 3.0 mg/kg dose groups of male and female mice. Non-neoplastic lesions occurred in the liver and kidney of male and female, and lung and arteries of female mice. These studies demonstrate toxicity and carcinogenicity of riddelliine in rats and mice, and a dose-response relationship in female rats and male mice under the experimental conditions employed.     

Development of a short-term model of decalin inhalation nephrotoxicity in the male rat

Fischer 344 male rats and C57BL/6 male mice were exposed 'continuously' (22 hr/day, 7 days/wk) for 20, 28 or 35 days to a model compound, decalin, at 0, 25, 62.5 or 125 ppm. Fischer 344 female rats were exposed 'continuously' to decalin at 0 or 125 ppm for 28 days. No histopathological changes were observed in selected organs of female rats or male mice exposed to up to 125 ppm decalin for 28 or 35 days, respectively. However, kidney lesions were observed in all three test groups of male rats after 20, 28 and 35 days' exposure. The nephrotoxicity was characterized by the formation of hyaline droplets in the cytoplasm of proximal convoluted tubule epithelial cells, by the presence of granular casts at the outer zone of the medulla, and by chronic nephrosis. These changes were time and dose dependent and were identical to the renal toxicity that has been reported to occur in male rats following 90 days of continuous exposure to decalin by inhalation. No histopathological effects were observed in the heart, liver, lung or nasal turbinates of male rats. Our results indicate a sex and species specificity for the kidney toxicity. This leads to questions with regard to the appropriateness of using the male rat to assess the potential inhalation toxicity of volatile hydrocarbons. By producing nephrotoxicity in less than 90 days, decalin may now be used to examine, in a well-defined manner, the effect on nephrotoxicity of variables such as dose, exposure regimen, sex, species, and route of exposure. Data from these studies can be used to ascertain whether or not the male rat is an appropriate test animal for predicting potential human nephrotoxic responses to volatile chemicals such as perfumes and perfume raw materials.     

Catalytic activity and inhibition of carbonic anhydrase of rat tissues

Carbonic anhydrase activity was studied in stomach and kidney homogenates, and isoenzymes were purified from erythrocytes and livers of male and female rats. Two liver isoenzymes of male and female rats and one erythrocyte isoenzyme had low CO₂ hydration activity. The enzymes of stomach and kidney, one isoenzyme of erythrocytes and one of female rat liver had high CO₂ hydration activity. The esterase activity toward p-nitrophenyl acetate paralleled the CO₂ hydration activity of all the isoenzymes. However, the esterase activity toward β-naphthyl acetate was either absent or did not show any correlation with the CO₂ hydration activity of isoenzymes. Male rat liver carbonic anhydrases were 1000 times less sensitive to sulfonamides than female rat liver carbonic anhydrases for the inhibition both of CO₂ hydration and esterase activity. Male rat liver carbonic anhydrases were as sensitive to inhibition by monovalent anions as were the female rat liver carbonic anhydrases. It is concluded that the active site of carbonic anhydrases from male rat liver is more hydrophilic than the active site of carbonic anhydrase from female rat liver or other tissues of the rat.     

Induction of aryl hydrocarbon hydroxylase by 3-methylcholanthrene in liver,lung and kidney of gonadectomized and sham-operated wistar rats

Detailed dose-response curves have been obtained for the induction of aryl hydrocarbon hydroxylase (AHH) m liver, lung and kidney by intraperitoneally administered 3-methylcholanthrene (3-MC) in Wistar rats. The effects of gonadectomy also were studied. Lung was the tissue most sensitive to induction, followed by liver, and then kidney in all cases. Although liver exhibited the greatest overall activity, the per cent increase over control AHH levels was much higher in the two extrahepatic tissues. Gonadectomy did not affect either control or induced AHH activity in any of the three organs in the female, or in the male lung. However, castration of the males decreased control liver enzyme levels and increased these levels in kidney. The AHH levels reached after maximal 3-MC induction were the same in castrated and sham-operated male rat livers. A different pattern was seen in male kidney enzyme levels where significantly increased maximal induction was observed in castrated animals.     

性别差异对异补骨脂素在大鼠体内吸收和分布的影响

目的：目的研究异补骨脂素（iopsoralen,IPO）在雌雄大鼠体内药动学和组织分布特征,探讨性别差异对IPO体内吸收和分布的影响。方法：通过单次灌胃给予雌雄大鼠80 mg·kg^-1IPO溶液,采用HPLC法测定不同时间点雌雄大鼠血浆和主要脏器（肝、肾、心、脾、肺）中IPO的含量,应用DAS 2.0计算主要药动学参数、SPSS 19.0进行统计学分析。结果：血浆药动学结果发现,雌雄大鼠血浆中IPO浓度变化趋势基本一致,但雌鼠血浆中AUC显著高于雄鼠。组织分布结果发现,IPO在雌雄大鼠肝肾组织中暴露量高于其他组织,其中IPO在雌鼠肝脏中AUC_0-t为（1 439.08±84.27） mg·h·L^-1,显著高于雄鼠（1 239.55±26.25） mg·h·L^-1（P<0.05）。结论：IPO在雌雄大鼠体内进程存在显著性别差异,主要表现为雌性大鼠血浆和肝组织中暴露量显著高于雄鼠,这可能是IPO易引起雌性大鼠肝损伤的原因。     

Toxicology and carcinogenesis studies of riddelliine (CAS No. 23246-96-0) in F344/N rats and B6C3F1 mice (gavage studies)

Riddelliine belongs to a class of toxic pyrrolizidine alkaloids and is isolated from plants of the genera Crotalaria, Amsinckia, and Senecio that grow in the western United States. Cattle, horses, and sheep that ingest these plants succumb to their toxic effects. Riddelliine residues have been found in meat, milk, and honey, and the plants may contaminate human food sources. Riddelliine was nominated for study by the Food and Drug Administration because of its potential for human exposure and its economic impact on the livestock industry and because the toxicity of other pyrrolizidine alkaloids suggests riddelliine may be carcinogenic. Male and female F344/N rats and B6C3F1 mice received riddelliine (approximately 92% pure) by gavage. Female rats and male and female mice were dosed for 2 years; due to high mortality, the study in male rats was terminated at week 72. In vitro genetic toxicology studies were conducted in Salmonella typhimurium and in cultured Chinese hamster ovary (CHO) cells. In addition, riddelliine was evaluated in vivo for induction of micronuclei in mouse bone marrow and peripheral blood erythrocytes and for induction of S-phase DNA synthesis and unscheduled DNA synthesis in the liver of rats and mice. Riddelliine-induced DNA adduct levels were determined in liver tissue obtained from female rats admininstered riddelliine for 3 or 6 months. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0 or 1 mg riddelliine/kg body weight in sodium phosphate buffer by gavage 5 days per week; additional groups of 50 female rats received 0.01, 0.033, 0.1, or 0.33 mg/kg. A wide dose range was used in female rats to better characterize the dose-response curve. Females were dosed for 105 weeks; due to high mortality, male rats were terminated at week 72. All but three 1 mg/kg males died before week 70, and all 1 mg/kg females died before week 97. Mean body weights of 1 mg/kg males and females were less than those of the vehicle controls throughout most of the study. The only clinical finding related to riddelliine administration was a general debilitation of the animals prior to death. Hemangiosarcomas were present in the liver of 86% of males and 76% of females in the 1 mg/kg groups, and this neoplasm was considered the cause of the large number of early deaths in these groups. The incidences of hepatocellular adenoma and mononuclear cell leukemia in 1 mg/kg males and females were significantly increased. Nonneoplastic lesions related to riddelliine treatment occurred in the liver and kidney of males and females. Analyses of liver tissue from female rats treated with riddelliine for 3 or 6 months yielded eight DNA adducts; these were the same as DNA adducts formed in vitro by the metabolism of riddelliine by human liver microsomes in the presence of calf thymus DNA. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered riddelliine in sodium phosphate buffer by gavage at doses of 0 or 3 mg/kg, 5 days per week, for 105 weeks; additional groups of 50 male mice received 0.1, 0.3, or 1 mg/kg for 105 weeks. A wide dose range was used in male mice to better characterize the dose-response curve. Survival of males and females administered 3 mg/kg was significantly less than that of the vehicle controls. Mean body weights of 3 mg/kg mice were less than those of the vehicle controls throughout most of the study. Hemangiosarcomas of the liver were present in 62% of males in the 3 mg/kg group. The incidences of hepatocellular neoplasms occurred with negative trends in male mice and were significantly decreased in 3 mg/kg females. The incidences of alveolar/bronchiolar neoplasms in 3 mg/kg females were significantly increased. Nonneoplastic lesions related to riddelliine administration occurred in the liver and kidney of males and females and in the lung and arteries (multiple tissues) of females. GENETIC TOXICOLOGY: Riddelliine was mutagenic in S. typhimurium strain TA100 with, but not without, S9 activation; no significant mutagenic activity was detected in strain TA98 or TA1535,ed in strain TA98 or TA1535, with or without S9. A small, dose-related increase in mutant colonies seen in strain TA97 with S9 was judged to be equivocal. Riddelliine induced sister chromatid exchanges in cultured CHO cells with and without S9. Chromosomal aberrations were induced in CHO cells only in the presence of S9. Following 4 or 13 weeks of daily gavage treatment with riddelliine, no increases in the frequency of micronucleated erythrocytes were noted in the peripheral blood of male or female B6C3F1 mice. Use of a single intraperitoneal injection protocol, however, produced a small but significant increase in the frequency of micronucleated eryth-rocytes in peripheral blood of male Swiss mice 48 hours after injection; bone marrow analysis 24 hours after injection demonstrated a small but insignificant increase in the frequency of micronuclei. Unscheduled DNA synthesis was detected in cultured hepatocytes from male and female rats and mice following 5 or 30 days of riddelliine treatment by gavage. In addition, an S-phase DNA synthesis was observed in cultured hepatocytes of male and female rats treated for either time period. CONCLUSIONS: Under the conditions of these studies, there was clear evidence of carcinogenic activity of riddelliine in male and female F344/N rats based primarily on increased incidences of hemangiosarcoma in the liver. The increased incidences of hepatocellular adenoma and mononuclear cell leukemia in male and female rats were also considered to be treatment related. There was clear evidence of carcinogenic activity of riddelliine in male B6C3F1 mice based on increased incidences of hemangiosarcoma in the liver. There was clear evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms. Administration of riddelliine by gavage resulted in nonneoplastic lesions in the liver and kidney of male and female rats; the liver and kidney of male and female mice; and the lung and arteries (multiple tissues) of female mice. Decreased incidences of hepatocellular neoplasms in male and female mice were related to riddelliine administration.     

Subchronic Toxicity Evaluation of Tridecyl Acetate in Rats

Subchronic Toxicity Evaluation of Tridecyl Acetate in Rats.DAUGHTREY, W. C, SMITH, J. H., HINZ, J. P., AND BILES, R. W.(1990). Fundam. Appl. Toxicol. 14, 104–112. Tridecyl acetatewas administered to male and female Sprague-Dawley rats by oralgavage, 5 days per week for 13 weeks (90 days). Treated ratsreceived daily doses of 0.1, 0.5, or 1.0 g/kg/day and controlrats received distilled water at a dose of 1.0 g/kg/day. After45 days an interim termination was made to evaluate potentialhematologic or hepatic effects of tridecyl acetate. Blood sampleswere collected for routine hematology and serum chemistry determinationsand liver tissue was obtained for histological examination.After 90 days all animals were necropsied. Blood samples wereobtained and selected organs were weighed and prepared for histologicalexamination. Treatment-related effects observed in the mid andhigh dose groups consisted of (1) increased liver weights and/orliver/body weight ratios in both sexes at the interim and 13week termination, (2) increased kidney weights and/or kidney/bodyweight ratios in both sexes at the terminal necropsy, (3) histopathologicevidence of hydrocarbon nephropathy in males, and (4) a slightdecrease in serum glucose levels in male rats at both the interimand terminal necropsies. The increases in liver weight are believedto be a normal physiological response to a chemkal challenge.The nephropathy produced by tridecyl acetate is characteristicof that produced by a diverse group of hydrocarbons and, todate, appears to be limited to male rats. The low dose in thisstudy was a no observed effect level. These results are indicativeof an overall low degree of systemic toxicity following subchronicoral administration of tridecyl acetate at doses up to 1 g/kgbody weight.     

Distribution and inducibility of cytosolic epoxide hydrolase in male Sprague-Dawley rats

Cytosolic epoxide hydrolase (cEH) activity has been determined in liver and various extrahepatic tissues of male Sprague-Dawley rats using trans-stilbene oxide (TSO) and trans-ethylstyrene oxide (TESO) as substrates. Large interindividual differences in the specific activity of cytosolic epoxide hydrolase in the liver from more than 80 individual rats were observed varying by a factor of 38. In a randomly selected group of five animals liver cEH varied by a factor of 3.9 and kidney cEH by a factor of 2.7, whereas liver microsomal epoxide hydrolase and lactate dehydrogenase showed only very low variations (1.4- and 1.1-fold, respectively). The individual relative activity of kidney cEH was related to that of the liver. Cytosolic epoxide hydrolase activity was present in all of six extrahepatic rat tissues investigated. Interestingly specific activities were very high in the heart and kidney (higher than in liver), followed by liver greater than brain greater than lung greater than testis greater than spleen. TSO and TESO hydrolases in subcellular fractions of rat liver were present at highest specific activities in the cytosolic and the heavy mitochondrial fraction. As indicated by the marker enzymes, catalase, urate oxidase and cytochrome oxidase, this organelle-bound epoxide hydrolase activity may be of peroxisomal and/or mitochondrial origin. In the microsomal fraction, TSO and TESO hydrolase activity is very low, whereas STO hydrolase activity is highest in this fraction and very low in cytosol. In kidney, subcellular distribution is similar to that observed in liver. None of the commonly used inducers of xenobiotic metabolizing enzymes caused significant changes in the specific activities of rat hepatic cEH (trans-stilbene oxide, alpha-pregnenolone carbonitrile, 3-methylcholanthrene, beta-naphthoflavone, isosafrole, butylated hydroxytoluene, 2,3,7,8-tetrachlorodibenzo-p-dioxin, dibenzo[a,h]anthracene, phenobarbitone). However, clofibrate, a hypolipidemic agent, very strongly induced rat liver cEH (about 5-fold), whereas microsomal epoxide hydrolase activity was not affected. Specific activity of kidney cEH was increased about 2-fold.     

Effect of tobacco-leaf extract administration on liver,lung, intestine,and serum enzymes

Tobacco-leaf extract induced benzpyrene hydroxylase activities of liver and lung of male albino rats after 7, 30, and 62 days of oral administration. Aniline hydroxylase activity of liver and lung showed an increase after 30 days of administration, while the N-demethylase activity of liver showed a small increase at the first phase and a decrease after 62 days. Of the lysosomal enzymes investigated, β-glucuronidase activity of both liver and lung showed a significant increase. Increased activities of hepatic lysosomal acid phosphatase was observed at 7 and 30 days of leaf-extract administration. A decrease was observed in sucrase and maltase activities of intestinal brush border after 7 and 30 days of tobacco-leaf extract administration. No significant change in serum enzymes was observed under the conditions of the present study.     

Inhalation toxicity of dimethyl piperidinone

A mixture of 1,3-dimethyl-2-piperidinone and 1,5-dimethyl-2-piperidinone (DMPD) (approximately 63-37 parts by weight) was tested for its inhalation toxicity in rats following 90-day repeated exposures. Male and female rats were exposed whole-body to either 0, 51, 230, or 310 mg/m(3) DMPD for 6 h/day, 5 days/weak for 90 days. Clinical signs, growth, clinical pathology, tissue pathology, neurobehavior, neuropathology, and semen quality were evaluated. No compound-related adverse effects were noted in clinical signs, body weights, food consumption, clinical laboratory evaluations, neurobehavioral evaluations, neuropathology, or sperm counts. Laryngeal changes consisting of minimal squamous epithelial hyperplasia and degeneration/necrosis of the cartilage were present in male and female rats exposed to 310 mg/m(3) both immediately following exposure and after the 1-month recovery period Male rats exposed to DMPD had increased relative kidney weights, increased formation of hyaline droplets and granular casts, and increased incidence of chronic progressive nephropathy. These kidney effects are consistent with increased accumulation of the urinary protein alpha(2 mu)-globulin, which has been well essential for several xenobiotics. The subsequent increased incidence of progressive nephropathy was specific to male rats with the alpha(2 mu) syndrome. Male and female rats exposed to 230 or 310 mg/m(3) had centrilobular hepatocellular hypertrophy, and male rats exposed to 310 mg/m(3) had increased relative liver weights. These liver changes were reversible following the recovery period and were considered not to represent adverse toxicological effects of treatment. Since the male rat-specific renal findings do not connote adversity for man and are net considered relevant to human hazard assessment, the no-observed-effect level in male and female rats was 230 mg/m(3), based on the microscopic changes in the larynx exposed to 310 mg/m(3).