Biochemical characterization,anti-inflammatory properties and ulcerogenic traits of some cold-pressed oils in experimental animals

Context: Cold-pressed oils (CPO) are commercially available in the market and characterized by their health-promoting properties.

Objective: Clove oil (CLO), coriander seed oil (COO) and black cumin oil (BCO) were evaluated for their bioactive lipids. Pharmacological screening was performed to evaluate acute toxicity, anti-inflammatory and ulcerogenic effects as well as histopathological changes in tissues of albino rats fed with CPO.

Materials and methods: Fatty acids, tocols and total phenolics were analyzed. The acute toxicity test for each CPO was estimated during 14 d. Carrageenan-induced rat paw oedema was used for assessment of anti-inflammatory activity of CPO. Animals were fasted overnight, and via oral gavage given indomethacin (10?mg/kg) or CPO (400?mg/kg) to investigate ulcerogenecity. Histopathological changes in liver, kidney, heart, spleen and stomach were screened.

Results: Amounts of α-, β-, γ- and δ-tocopherols in CLO were 1495, 58, 4177 and 177?mg/kg oil, respectively. In COO, α, β, γ and δ-tocopherols were 10.0, 18.2, 5.1 and 34.8%, respectively. In BCO, β-tocotrienol was the main constituent. CLO, COO and BCO contained 4.6, 4.2 and 3.6?mg GAE/g, respectively. Acute toxicity test determined that 400?mg/kg of CPO to be used. In the carrageenan model of inflammation, pretreatment of rats with indomethacin (10?mg/kg) or CLO (400?mg/kg) induced a significant (p?Conclusions: CPO, particularly CLO, could minimize acute inflammation.     

Effect of clofibrate feeding on palmitate and branched-chain 2-oxo acid oxidation in rat liver and muscle

Oxidation rates of palmitate (total and antimycin-insensitive), pyruvate, leucine, 4-methyl-2-oxopentanoate and 3-methyl-2-oxobutanoate and activities of two mitochondrial marker enzymes (citrate synthase and cytochrome c oxidase) were assayed in liver and muscle homogenates of fed, clofibrate-treated and 18 hr-starved rats. Significant alterations in the clofibrate-treated and the starved rats were predominantly observed in the liver. Clofibrate feeding increased antimycin-insensitive (peroxisomal) and antimycin-sensitive (mitochondrial) palmitate oxidation and 4-methyl-2-oxopentanoate and pyruvate oxidation in liver. In muscle, only the activities of citrate synthase and cytochrome c oxidase were slightly decreased. Short starvation increased antimycin-sensitive palmitate and 4-methyl-2-oxopentanoate oxidation in liver. The rates of pyruvate and 3-methyl-2-oxobutanoate oxidation were decreased in muscle homogenates. Results suggest that myopathic phenomena observed after chronic clofibrate administration are not related to changes in the capacity of oxidative metabolism of muscle.     

Toxic Interactions Between Fungicides That Inhibit Ergosterol Biosynthesis and Phosphorothioate Insecticides in the Male Rat and Bobwhite Quail (Colinus virginianus)

The potential for toxic interactions between ergosterol biosynthesis-inhibiting fungicides (EBIFs), used in U.S. agriculture or clinically, and phosphorothioate insecticides was assessed in adult male rats and adult male bobwhite quail (Colinus virginianus) by measuring inhibition of plasma butyryl cholinesterase (BChE) following fungicide and insecticide treatment. Male Sprague-Dawley rats (300 g) were administered corn oil or the following EBIFs: propiconazole (400 mg/kg/day), vinclozolin (400 mg/kg/day), clotrimazole (100 mg/kg/day), or ketoconazole (100 mg/kg/day) for 3 days by oral gavage. Forty-eight hours following the final dose, a single bolus of parathion (0.4 mg/kg in corn oil) or malathion (150 mg/kg in corn oil) or corn oil alone was given po. The rats were terminated 12 hr following parathion or 4 hr following malathion dosing. Significant (p < 0.05) inhibition of BChE was observed with parathion and malathion only following clotrimazole treatment. In contrast, when a similar experiment was performed in bobwhite quail dosed with 12 mg/kg malathion following EBIF treatment, significant BChE inhibition was observed following treatment with vinclozolin or ketoconazole, but not with propiconazole or clotrimazole. Induction of cytochrome P450 in rat and quail liver by EBIFs was accompanied by enhanced oxidative desulfuration of malathion, parathion, and diazinon to toxic oxon products. Increased detoxication via oxidative dearylation/esterolytic clevage also occurred. However, while enhanced acute in vivo insecticide toxicity was observed in both species with a number of EBIF-phosphorothioate combinations, EBIF-induced oxidative activation of phosphorothioates by liver microsomes in vitro was not a good predictor of this effect.     

Ten- and ninety-day toxicity studies of 1,2-dichlorobenzene administered by oral gavage to Sprague-Dawley rats

Ten- and ninety-day toxicity studies of 1,2-dichlorobenzene (DCB) were conducted in male and female Sprague-Dawley rats to meet the needs of the U.S. Environmental Protection Agency for toxicity data on this chemical for use in their determination of possible health risks related to human exposure. 1,2-Dichlorobenzene was administered at doses of 37.5, 75, 150, and 300 mg/kg/day (10-day), and 25, 100, and 400 mg/kg/day (90-day) in corn oil by oral gavage; control animals received corn oil. At time of sacrifice, gross necropsies were performed and selected tissues were weighed and prepared for histological evaluation. Blood was taken for hematology and clinical chemistries. In the 10-day study, exposure of 300 mg DCB/kg body weight to male rats resulted in a statistically significant decrease in final body weight, organ weights (heart, kidneys, spleen, testes, and thymus), and relative organ weights (spleen and thymus). A significant increase in absolute and relative liver weights was also noted in this dose group. Males also displayed significant increases in water consumption (300 mg/kg group), ALT (300 mg/kg) and leukocyte count (150 and 300 mg/kg). A significant increase in the incidence of hepatocellular necrosis was seen in the 300 mg/kg group of males compared to controls. In the 90-day study, male rats exposed to 400 mg DCB/kg displayed a statistically significant decrease in body weight, organ weight (spleen), and relative organ weight (spleen). The absolute weights of kidney and liver and the relative weights for heart, kidney, liver, lung, brain, and testes were increased significantly for this dose group. The absolute and relative weights of both the kidney and liver were significantly increased in the female 400 mg/kg dose group. The only clinical chemistry parameters statistically different than control were increased ALT (100 and 400 mg/kg groups), BUN and total bilirubin in the male 400 mg/kg group and total bilirubin in the 400 mg/kg female group. Histopathological evaluation showed hepatocellular lesions associated with DCB treatment which included centrolobular degeneration and hypertrophy, and single cell necrosis in male and females receiving 400 mg DCB/kg. The NOAEL observed in this study is 25 mg/kg/day.     

Short-term toxicity study in rats dosed with menthone

Menthone, a component of peppermint oil, was given p.o. to groups of 10 male and 10 female rats at dose levels of 0, 200, 400 and 800 mg/kg b.w./day, respectively, for 28 days. After 19 days the dose was reduced to 400 mg/kg b.w. in the female group receiving the highest dose. Analyses of plasma showed a dose-dependent decrease in creatinine content and a dose-dependent increase in alkaline phosphatase activity and bilirubin. The relative weights of liver and spleen were increased. Cyst-like spaces were seen histopathologically in the white matter of the cerebellum of the two highest dose groups. The no-effect level for menthone in this study was lower than 200 mg/kg b.w./day.     

Kidney and Urinary Bladder Lesions in F344/N Rats and B6C3F1 Mice after 13 Weeks of 2,2-Bis(bromomethyl)-1,3-propanediol Administration

Kidney and Urinary Bladder Lesions in F344/N Rats and B6C3F1Mice after 13 Weeks of 2,2-Bis(bromomethyl)-1,3-propanediolAdministration. ELWELL., M. R., DUNNICK, J. K., BROWN, H. R.,AND MONTGOMERY, C. A. (1989). Fundam Appl. Toxicol. 12, 480–490.Thir teen-week toxicity studies of the flame retardant 2,2-bis(bromomethyl)-1,3-propanediol(BMP; dibromoneopentyl glycol; FR-1138; CAS No. 329690-0) wereconducted in male and female F344/N rats and B6C3F1 mice. Thechemical was administered by oral gavage in corn oil 5 daysper week for 13 weeks to rats at doses of 0, 50, 100, 200, 400,and 800 mg/kg and to mice at doses of 0, 25, 50, 100, 200, and400 mg/kg, or in the feed for 13 weeks at concentrations of0, 1250, 2500, 5000, 10,000, and 20,000 ppm for rats and at0, 625, 1250, 2500, 5000, and 10,000 ppm for mice. There wasa dose-related decrease in body weight gain in rats and miceafter chemical administration. Mortality attributed to toxicityof BMP was seen in the gavage study in 2/10 high-dose (800 mg/kg)male rats and 3/10 high-dose (400 mg/kg) male mice; no dose-relatedmortality occurred in the feed study. Minimal degeneration inthe renal papilla was seen in male rats at 800 mg/kg in thegavage study and at doses of 5000 ppm or more in the feed study.This was also present in one female rat at the 20,000 ppm dose.In male mice renal papillary necrosis occurred at 400 mg/kgafter dosing by the gavage route and at 2500, 5000, and 10,000ppm in the dosed-feed study. In female mice papillary necrosisoccurred only at the 10,000 ppm dose in the feed study. Tubularcell regeneration of the renal cortex was also present in miceat the same dose levels at which the papillary necrosis wasobserved. Transitional cell hyperplasia of the urinary bladderwas seen in male rats at 400 and 800 mg/kg and in both sexesof mice at 200 and 400 mg/kg. Hyperplasia of the urinary bladderwas also seen when BMP was administered in the feed at dosesof 20,000 ppm to male rats; at doses of 2500, 5000, and 10,000ppm to male mice; and at doses of 5000 and 10,000 ppm to femalemice. The kidney and urinary bladder are target organs whenBMP is administered by gavage or the dosed-feed route; micewere more sensitive than rats for the development of kidneyand bladder lesions. Male rats and mice were more sensitivethan females for the development of renal papillary degenerationor necrosis.     

Short term toxicity study in rats dosed with pulegone and menthol

Pulegone and menthol, components of peppermint oil, were investigated in rats. The substances were administered by gavage for 28 days at 0, 20, 80, 160 mg pulegone and 0, 200, 400, 800 mg menthol/kg body wt./day, respectively. At the two highest doses, pulegone induced atonia, decreased blood creatinine content, lowered terminal body weight and caused histopathological changes in the liver and in the white matter of cerebellum. For menthol at all dose levels a significant increase in absolute and relative liver weights and vacuolisation of hepatocytes was found. No sign of encephalopathy was observed in rats given menthol.The no effect level for pulegone was 20 mg/kg body wt./day and for menthol < 200 mg/kg body wt./day.     

The effect of different diets or mineral oil on liver pathology and polybrominated biphenyl concentration in tissues

Groups of 10 adult (3.5 months) male Sherman strain rats were given 0 or a single dose of 500 mg polybrominated biphenyls (PBB) in corn oil/kg by stomach tube. Three weeks later, groups of 10 rats each that had received 500 mg/kg and groups of 10 rats each that had been given corn oil were started on a purified 20% fiber or 4% fiber diet. Ten rats each that had received 500 mg/kg or corn oil were continued on Purina Chow. An additional group of 10 rats given 500 mg/kg was also continued on Purina Chow but was given 2 ml mineral oil/kg three times a week. All rats were given the different diets or the mineral oil for 3 months. Chemical analysis of blood, liver, and adipose tissue by gas chromatography for PBBs showed no statistically significant difference in the PBB concentrations in blood and adipose tissue among the different groups. The PBB concentrations in the liver of rats fed Purina Chow were significantly lower than in the other groups if they were calculated on a wet weight basis. When PBB concentrations in liver were calculated on a lipid basis, the differences were not statistically significant. Total liver lipids showed statistically significant increases in rats given 500 mg/kg followed by 4 or 20% purified fiber diet or by Purina Chow and 2 ml of mineral oil/kg every other day. Microscopic examination of the livers showed essentially normal parenchyma in all rats that had not received PBBs. The rats given a single oral dose of 500 mg/kg which was followed by Purina Chow or Purina Chow and mineral oil showed some centrolobular vacuolated hepatocytes and enlarged hepatocytes around the central veins. The vacuolation was more pronounced in rats receiving Purina Chow and mineral oil also. Rats given 500 mg/kg followed by 4 or 20% purified fiber diet showed severe steatosis of the liver with megalo-hepatocytes, areas of cell necrosis and interstitial fibrosis. The interstitial fibrosis was more pronounced in rats given the 20% purified fiber diet. These results indicate a pronounced additive effect on PBB liver toxicity in rats by the 4 or 20% purified fiber diets which may be deficient in some nutrients or may prevent absorption of important nutrients.     

Subchronic oral toxicity study with cyadox in Wistar rats.

To investigate the potential subchronic toxicity of cyadox, groups of 15 male and 15 female Wistar rats were fed with diets containing cyadox (0, 50, 150 or 2500 mg/kg) or olaquindox (150 mg/kg), approximately equivalent to cyadox 5, 15, 250 or olaquindox 15 mg/kg b.w./day, for 13 weeks. Five rats/sex/group were sacrificed on days 30, 60 and 90. No test-material-related changes were seen in mortality, clinical signs, hematology, clinical chemistry, organ weight data and macroscopic examinations. Except that body weights of both sexes of the 2500 mg/kg cyadox group were significantly lower than controls beginning after the second week of treatment. Body weights of females of 150 mg/kg olaquindox group were significantly lower than those of the control group at weeks 3 and 4. Other groups were unaffected by treatments. Histopathological observations revealed that 2500 mg/kg cyadox or 150 mg/kg olaquindox induced swelling and fatty degeneration of the hepatocytes and proximal renal tubular epithelial cells. It was for the first time that changes were found in the liver and kidneys of rats fed 2500 mg/kg cyadox. The no-observed-adverse-effect level (NOAEL) of cyadox for rats was estimated to be 150 mg/kg dietary dose level.     

Phenthoate toxicity: cumulative effects in rats

This study was designed to provide information on the cumulative effects of phenthoate, an organophosphorus insecticide. Male rats were given the test compound orally 6 days/week for a minimum of 10 weeks and until the cumulative LD50 (CLD50) remained constant for 3 consecutive weeks. The oral LD50 value for phenthoate in rats was highest (116 mg/kg) in groundnut oil followed by dimethylsulfoxide (DMSO) and alcohol. The animals with lesser weight were more susceptible than the heavier animals. Rats receiving 2.5 to 10 mg/kg phenthoate for 13 weeks showed varying decreases in weights of liver, heart, spleen, brain, testes and adrenals. At 40 mg/kg, none of the animals survived. The CDL50 for 13 weeks was 12 mg/kg with a cumulative toxicity factor of 6.3. The compound has been rated as a moderately hazardous one.     

Acute Hepatotoxic and Nephrotoxic Effects of Chloroform in Male F-344 Rats and Female B6C3F1 Mice

Previous studies demonstrated that chloroform given by oralgavage in corn oil caused an increased incidence of liver tumorsin male and female mice and kidney tumors in male rats, whileadministration in drinking water resulted in an increased tumorincidence only in the kidneys of the male rats. The tumorigenicityof this nongenotoxic agent has been postulated to be linkedwith cytolethality and cell proliferation. This study examinedthe organ-specific toxicity of acute doses of chloroform. MaleF-344 rats were given chloroform by gavage in corn oil at thebioassay doses of chloroform of 0 and 180 mg/kg body wt as wellas 34 and 477 mg/kg and necropsied 24 hr later. Additional ratswere given a single dose of 180 mg chloroform/kg and administeredbromodeoxyuridine (BRDU) 2 hr prior to necropsy at 0.5, 1, 2,4, and 8 days after chloroform treatment. Female B6C3F1 micewere given chloroform by gavage at the bioassay doses of 0,238, and 477 mg/kg as well as 34 mg/kg and necropsied at 24hr after treatment. Additional mice were given a single doseof 350 mg chloroform/kg, labeled with BRDU, and necropsied at0.5, 1, 2, 4, and 8 days after treatment. The kidneys of malerats administered 34, 180, and 477 mg chloroform/kg exhibitedmild to severe proximal tubular necrosis in a dose-dependentmanner. A 20-fold increase in the labeling index (LI, the percentageof nuclei in S-phase) in the proximal tubule cells was observed2 days after treatment with the bioassay dose of 180 mg/kg.The livers of male rats exhibited only slight to moderate multifocalcentrilobular necrosis at 180 and 477 mg/kg. A 10-fold increasein the LI was observed in the liver of male rats given 477 mg/kg,but no increase was observed at the bioassay dose of 180 mg/kg.In contrast to male rats, female mice developed a dose-dependentcentrilobular hepatic necrosis at 238 and 477 mg/kg. No renallesions were observed in female mice at any dose. A peak increasein LI of 38-fold was observed in hepa-tocytes in the liversof female mice 2 days after treatment with 350 mg chloroform/kg,with only a 2-fold increase in LI observed in the kidneys. Thesedata indicate that acute chloroform-induced cytolethality leadsto increased cell proliferation and that the organ-specificpattern of toxicity is the same as the organ-specific patternof tumor formation. These observations are suggestive of a rolefor induced cell proliferation in tumor formation and indicatethat more extensive cell proliferation Studies are Warranted.     

Antioxidant effect of onion oil (Allium cepa. Linn) on the damages induced by nicotine in rats as compared to alpha-tocopherol

The beneficial effects of onion oil as an antioxidant has been assessed in nicotine administered rats by studying whether the peroxidative damage caused by nicotine can be effectively combated with the onion oil and the effects compared to vitamin E, a highly efficient antioxidant. Lipid peroxidation products and antioxidant defence system have been studied in liver, lungs, and heart. The rats were injected with nicotine (0.6 mg/kg body wt.) and simultaneously given onion oil (100 mg/kg body wt.) or vitamin E (100 mg/kg body wt.) for 21 days. Concentration of free fatty acids, TBA reactive substances (TBARS), conjugated dienes and hydroperoxides were significantly increased in the tissues of nicotine treated rats as compared to normal rats. Onion oil supplemented to nicotine treated rats showed increased resistance to lipid peroxidation and the effect was near to that of vitamin E fed rats. The activity of catalase and superoxide dismutase decreased in nicotine treated rats. Antioxidants-glutathione content, vitamin C and retinol showed no significant difference but liver vitamin E content significantly decreased in nicotine treated rats. On onion oil or vitamin E supplementation, the concentration of antioxidants were significantly raised in all the tissues studied, however, a significantly increased concentration of glutathione, vitamin E and retinol was noticed in vitamin E+nicotine treated rats. Thus, these results indicate that onion oil is an effective antioxidant against the oxidative damage caused by nicotine as compared to vitamin E.     

Toxicological evaluation of 4-vinylcyclohexene. I. Prechronic (14-day) and subchronic (13-week) gavage studies in Fischer 344 rats and B6C3F1 mice

4-Vinylcyclohexene (VCH), a dimer of 1,3-butadiene present in the gases discharged during tire curing, was examined for its toxic effects in Fischer 344 (F344) rats and B6C3F1 mice by 14-d prechronic and 13-wk subchronic testing. In the 14-d studies, VCH was administered orally by gavage in corn oil at doses of 0 (vehicle control), 300, 600, 1250, 2500, or 5000 mg/kg body weight to groups of five F344 rats and B6C3F1 mice of each sex, while the doses for the 13-wk studies (10 animals/group; 5 d/wk) were 0 (vehicle control), 50, 100, 200, 400, or 800 mg/kg body weight for rats and 0 (vehicle control), 75, 150, 300, 600, or 1200 mg/kg body weight for mice. All rats and most mice in the 14-d studies died when administered doses greater than or equal to 1250 mg/kg, although no compound-related gross or histopathologic effects were observed. In the 13-wk studies, extensive mortality was observed only in mice dosed at 1200 mg/kg. Final body weights were reduced in the 13-wk studies in male rats receiving doses greater than or equal to 400 mg VCH/kg, in female rats receiving 800 mg/kg, and in female mice receiving 600 mg/kg. Compound-related histopathologic effects in the 13-wk studies included hyaline droplet degeneration of the proximal convoluted tubules of the kidney in dosed male rats, the severity of which was dose-related, and a reduction in the number of primary follicles and mature graafian follicles in the ovaries of female mice receiving 1200 mg VCH/kg. No compound-related gross or histopathologic effects were evident in dosed female rats or male mice in the 13-wk studies.     

Metabolic alterations after chronic exposure to -chlordane

Daily injection of α-chlordane (5 mg/kg) for 45 days significantly stimulated the activities of pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-diphosphatase and glucose-6-phosphatase in liver and kidney cortex of male rats. Statistically significant increases in the quartet of the key, rate-limiting gluconeogenic enzymes in two tissues were noted within 20 days when the daily amount of α-chlordane was raised to 25 mg/kg. Long-term exposure to either dose of the insecticide for 45 days also elevated the concentration of serum urea. The present results together with our previous findings suggest that chronic administration of α-chlordane is as effective as DDT in enhancing the gluconeogenic capacity of both kidney cortex and liver.     

A chronic toxicity study of cyadox in Wistar rats

To investigate the chronic toxicity of cyadox, a growth promoting agent, five groups of Wistar rats (30 rats/group/sex) were fed with the diets containing cyadox (0, 100, 400 and 2000 mg/kg) or olaquindox (400 mg/kg) for 78weeks. There were significant decreases in body weights in both genders during most of the study period in 2000 mg/kg cyadox and 400 mg/kg olaquindox rats. Significant decreases in serum alkaline aminotransferase in the 2000 mg/kg cyadox rats at weeks 26, 52 and 78 were observed. Relative weights of liver and kidney were significantly increased in 2000 mg/kg cyadox and 400 mg/kg olaquindox rats at weeks 26, 52 and 78. A significant increase in relative brain and heart weights in 2000 mg/kg cyadox males was observed. The histopathological examinations revealed that 2000 mg/kg cyadox diet or 400 mg/kg olaquindox diet could induce proliferation of bile canaliculi in the portal area of liver and swelling and fatty degeneration of the proximal renal tubular epithelial cells in kidneys. In conclusion, the target organs of cyadox for rats were liver and kidney. The no-observed-adverse-effect level of cyadox in this study was estimated to be 400 mg/kg diet.     

NMR-spectroscopy-based metabonomic approach to the analysis of Bay41-4109, a novel anti-HBV compound, induced hepatotoxicity in rats

An integrated metabonomics study using high-resolution (1)H nuclear magnetic resonance (NMR) spectroscopy has been applied to investigate the biochemical composition of urine, serum, liver tissue aqueous extracts (acetonitrile/water) and liver tissue lipidic extracts (chloroform/methanol) obtained from control and Bay41-4109 treated rats (10, 50, 400mg.kg(-1).d(-1) for 5 days, i.g.). Principal components analysis was used to visualize similarities and differences in biochemical profiles. The results showed the effects induced by Bay41-4109 at 400mg.kg(-1).d(-1) are different from those induced at 10, 50mg.kg(-1).d(-1). The biochemical profiles of 400mg.kg(-1).d(-1) group might reflect the hepatotoxicity of Bay41-4109 more exactly. The elevation in the level of 3-HB, lactate, 2-hydroxy-acetol and d-glucose was found in the urine, and the levels of VLDL/LDL(CH(2))(n), VLDL/LDL-CH(3), 2-oxo-3-methyl-n-valerate, 3-HB, lactate, acetate, taurine, 2-hydroxy-isovalerate in serum were increased significantly in 400mg.kg(-1).d(-1) group. The predominant changes identified in liver tissue aqueous extracts included an increase in the signal intensities of lactate, 3-amino-isovalerate, pyruvate, choline, trimethylamine-N-oxide (TMAO) and a reduction in the intensities of taurine, hippurate and d-glucose. In liver tissue chloroform/methanol extracts, there was a remarkably increase in many of the lipid signals including the triglyceride terminal methyl, methylene groups, and CH(2)CO, N(+)(CH(3))(3), CH(2)OPO(2), CH(2)OCOR. These observations all provide evidence that fatty acid metabolism disorder and mitochondrial inability might contribute to the hepatotoxicity of Bay41-4109. The application of (1)H NMR spectroscopy to an array of biological samples comprising urine, serum and liver tissue extracts yields new insight into the hepatotoxicity of xenobiotics.     

Toxicity and carcinogenicity of hydroquinone in F344/N rats and B6C3F1 mice.

Toxicology and carcinogenesis studies were conducted by administering hydroquinone (more than 99% pure) by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 wk or 2 yr. 14-day studies were conducted by administering hydroquinone in corn oil to rats at doses ranging from 63 to 1000 mg/kg body weight and to mice at doses ranging from 31 to 500 mg/kg, 5 days/wk. In the 13-wk studies, doses for rats and mice ranged from 25 to 400 mg/kg. At those doses showing some indication of toxicity in the 14-day and 13-wk studies, the central nervous system, forestomach and liver were identified as target organs in both species and renal toxicity was observed in rats. Based on these results, 2-yr studies were conducted by administering 0, 25 or 50 mg hydroquinone/kg in deionized water by gavage to groups of 65 rats of each sex, 5 days/wk. Groups of 65 mice of each sex were given 0, 50 or 100 mg/kg on the same schedule. 10 rats and 10 mice from each group were killed and evaluated after 15 months. Mean body weights of high-dose male rats and high-dose mice were approx. 5-14% lower than those of controls during the second half of the study. No differences in survival were observed between dosed and control groups of rats or mice. Nearly all male rats and most female rats in all vehicle control and exposed groups had nephropathy, which was judged to be more severe in high-dose male rats. Hyperplasia of the renal pelvic transitional epithelium and renal cortical cysts were increased in male rats. Tubular cell hyperplasia of the kidney was seen in two high-dose male rats, and renal tubular adenomas were seen in 4/55 low-dose and 8/55 high-dose male rats; none was seen in vehicle controls or in female rats. Mononuclear cell leukaemia in female rats occurred with increased incidences in the dosed groups (vehicle control, 9/55; low dose, 15/55; high dose, 22/55). Compound-related lesions observed in the liver of high-dose male mice included anisokaryosis, syncytial alteration and basophilic foci. The incidences of hepatocellular neoplasms, primarily adenomas, were increased in dosed female mice (3/55; 16/55; 13/55). Follicular cell hyperplasia of the thyroid gland was increased in dosed mice.(ABSTRACT TRUNCATED AT 400 WORDS)     

绞股兰总皂甙对鼠免疫功能的影响

绞股兰总皂甙对环磷酰胺所致小鼠血清溶血素减少、对皮质激素地塞米松所致大鼠脾脏空斑形成细胞(PFC),特异玫瑰花形成细胞(SRFC)和脾细胞抗体分泌量(QHS)减少及对荷S-180实体瘤小鼠PFC、SRFC和QHS减少均有明显保护作用。并能减轻环磷酰胺所致小鼠免疫器官的萎缩。这些结果表明绞股兰总皂甙对免疫反应低下动物有显著的免疫增强作用。     

硝硫氰胺在血吸虫病患者体内的清除和药物对大鼠肝胆系统毒性的研究

本文报告日本血吸虫病患者口服硝硫氰胺后,药物在体内的分布与清除及药物对大鼠肝胆系统的影响。硝硫氰胺350 mg分3天口服的47例血吸虫病患者,首次给药后48小时的全血药浓度的平均值为1.56±0.18 μg/ml。末次给药后16天,血药浓度还维持在0.10 μg/ml。但药物主要存在于血浆中,血细胞与其它有形成分的含药量则较少。给药期原药经由尿的排泄量大于停药后的排泄量,药物的排出可持续到19天以上。在一例因其它疾病死亡的尸检脏器组织中,测得肝、肾、心、脾的药物含量均高于肌肉、脑、脂肪与血清中的含药量。大鼠口服硝硫氰胺100 mg/kg/d×7,胆汁分泌量明显减少,与对照组比较胆汁量减少58.3%。药物能抑制肝脏分泌胆汁的能力,并使动物黄疸指数和胆红素升高。     

Effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor, on tissue carnitine and lipid levels in rats

MET-88, 3-(2,2,2-trimethylhydrazinium) propionate, suppresses carnitine synthesis by inhibiting (gamma-butyrobetaine hydroxylase. The purpose of this study was to clarify the effects of suppression of carnitine synthesis on carnitine and lipid contents in tissues. MET-88 (50, 100, 200 or 400 mg/kg/d) was administered orally to male SD rats for 10, 30 or 60 d. Total carnitine and lipid (triglycerides, non-esterified fatty acids) contents were measured in heart and liver. In both tissues, treatment with MET-88 dose-dependently decreased total carnitine levels, and the reduction reached the plateau state after 30 d at each dose. MET-88 had no effect on lipid content in the heart, but increased the lipid content in the liver at the highest doses. Treatment with MET-88 at 400 mg/kg for 60 d resulted in no pathologic findings in the histological study, and also had no effect on parameters of liver function such as glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase as judged from the results of blood biochemical analysis. We concluded that long-term treatment with MET-88 decreased the carnitine content to a constant level in both heart and liver, but had no effect on lipid contents in the heart, although it affected lipid metabolism in the liver.