Toxicokinetics of cinnamaldehyde in F344 rats

The toxicokinetic profile of cinnamaldehyde (CNMA) was investigated in Fischer 344 rats. CNMA was found to be unstable in blood. After iv administration, a large fraction of CNMA was immediately oxidized to cinnamic acid. The biological half-life of CNMA after iv administration was found to be 1.7 hr. After administration by gavage of CNMA at 250 or 500 mg/kg body weight using corn oil as vehicle, the maximum blood concentrations of CNMA were in the order of 1 μg/ml. These low blood concentrations were maintained over a 24-hr period after a dose of 500 mg/kg, which is relatively long considering the short (1.7 hr) biological half-life of CNMA. The estimated oral bioavailability of CNMA was less than 20% for both the 250 and 500 mg/kg doses. No CNMA was present in blood at any time in rats dosed with 50 mg CNMA/kg body weight. Only a small amount of the administered CNMA was excreted in rat urine as free cinnamic acid or β-glucuronide-conjugated cinnamic acid. The majority of CNMA administered orallywas excreted in urine as hippuric acid within 24 hr. The maximum excretion rate occurred at 8 hr after gavage. Hippuric acid recovered in 50-hr urine samples was found to be directly proportional to the oral dose of CNMA.     

An approach to the toxicity and toxicokinetics of aflatoxin B1 and ochratoxin A after simultaneous oral administration to fasted F344 rats

Humans are exposed to the hepatotoxic aflatoxin B1 (AFB1) and nephrotoxic ochratoxin A (OTA) through diet. However, kinetic and toxicological data after their co-administration are scarce.     

Gene expression changes induced by ochratoxin A in renal and hepatic tissues of male F344 rat after oral repeated administration

Ochratoxin A (OTA), a naturally occurring mycotoxin, is nephrotoxic in all animal species tested and is considered a potent renal carcinogen, particularly in male rats. Its mechanism of toxicity is still unknown, although oxidative stress appears to be a plausible mechanism. Therefore, the objective of this study was to identify the biological pathways that are modulated in vivo by OTA in male F344 rats in order to gain further insight into its mechanism of renal toxicity. Rats were gavaged daily with OTA (500 microg/kg bw) and gene expression profiles in target and non-target organs were analyzed after 7 and 21 days administration. As was expected, a time-dependent increase of OTA concentrations was found in plasma, kidney and liver, with the concentrations found in both tissues being quite similar. However, histopathological examinations only revealed changes in kidney; signs of nephrotoxicity involving single cell necrosis and karyomegalic nuclei were observed in the treated rats. The number of differentially expressed genes in kidney was much higher than in liver (541 versus 11 at both time points). Several similarities were observed with other in vivo gene expression data. However, great differences were found with previous in vitro gene expression data, with the exception of DNA damage response which was not observed at mRNA level in any of our study conditions. Down-regulation was the predominant effect. Oxidative stress response pathway and genes involved in metabolism and transport were inhibited at both time points. RGN (regucalcin) - a gene implicated in calcium homeostasis - was strongly inhibited at both time points and genes implicated in cell survival and proliferation were up-regulated at day 21. Moreover, translation factors and annexin genes were up-regulated at both time points. Apart from oxidative stress, alterations of the calcium homeostasis and cytoskeleton structure may be present at the first events of OTA toxicity.     

Toxicokinetics of the ciguatoxin P-CTX-1 in rats after intraperitoneal or oral administration

Diffusion-weighted imaging (DWI) allows the assessment of the water apparent diffusion coefficient (ADC), a measure of tissue water diffusivity which is altered during different pathological conditions such as cerebral oedema. By means of DWI, we repeatedly measured in the same rats apparent diffusion coefficient ADC in different brain areas (motor cortex (MCx), somato-sensory cortex (SCx), caudate-putamen (CPu), hippocampus (Hip), mesencephalic reticular formation (RF), corpus callosum (CC) and cerebellum (Cb)) after 1 week, 4 and 12 weeks of lead acetate exposure via drinking water (50 or 500 ppm). After 12 weeks of lead exposure rats received albumin-Evans blue complex administration and were sacrificed 1h later. Blood-brain barrier permeability and water tissue content were determined in order to evaluate their relationship with ADC changes. Chronic exposure to lead acetate (500 ppm) for 4 weeks increased ADC values in Hip, RF and Cb but no in other brain areas. After 12 weeks of lead acetate exposure at 500 ppm ADC is significantly increased also in CPu and CC. Brain areas displaying high ADC values after lead exposure showed also an increased water content and increased BBB permeability to Evans blue-albumin complex. Exposure to 50 ppm for 12 weeks increased ADC values and BBB permeability in the RF and Cb. In summary, chronic lead exposure induces cerebral oedema in the adult brain depending on the brain area and the dose of exposure. RF and Cb appeared the most sensitive brain areas whereas cerebral cortex appears resistant to lead-induced cerebral oedema.     

Toxicokinetics of 2-methylimidazole in male and female F344 rats

The toxicokinetics of 2-methylimidazole (2-MI) were studied in male and female Fischer 344 rats after a single iv dose of 10 mg/kg or gavage dose of 25, 50, or 100 mg/kg. The 2-MI was formulated in 0.05 M phosphate-buffered saline (pH 7.4). The iv profiles could be best described by a two-compartment model with first-order elimination. The terminal elimination half-life, volume of distribution at steady state, and clearance values were 0.78 and 0.85 h(-1), 1.5 and 1.9 L, and 4.97 and 12.0 L/h/kg for males and females, respectively. After a gavage dose, the plasma concentration time profiles could be best described by a one-compartment model, no lag phase, and first-order absorption and elimination. The peak 2-MI plasma concentrations increased proportionately with dose and were reached within 35 to 50 min (T(max)) for all groups. The estimated half-life value for 2-MI was about 1 h for the iv group and the male 25-, 50-, or 100-mg/kg groups and female 25-mg/kg groups. Clearance increased for the male 100- and female 50- and 100- mg/kg groups. For a given dose group, clearance was also two to three times greater for female rats when compared to male rats. Absolute bioavailability for 2-MI was estimated to approach 97%. The results of this study indicated that 2-MI was (1) rapidly and completely absorbed, (2) quickly eliminated, (3) cleared differently for females than for males, (4) affected somewhat by dose for females, and (5) unlikely to undergo tissue accumulation following repeated exposure.     

Toxicokinetics of tetrabromobisphenol a in humans and rats after oral administration.

Tetrabromobisphenol A (TBBPA) is widely used as a flame retardant and is suspected to be stable in the environment with possible widespread human exposures. This study reports the characterization of the toxicokinetics of TBBPA in human subjects and in rats. A single oral dose of 0.1 mg/kg TBBPA was administered to five human subjects. Rats were administered a single oral dose of 300 mg TBBPA/kg body weight. Urine and blood concentrations of TBBPA and its metabolites were determined by LC/MS-MS. TBBPA-glucuronide and TBBPA-sulfate were identified as metabolites of TBBPA in blood and urine of the human subjects and rats. In blood, TBBPA-glucuronide was detected in all human subjects, whereas TBBPA-sulfate was only present in blood from two individuals. Maximum plasma concentrations of TBBPA-glucuronide (16 nmol/l) were obtained within 4 h after administration. In two individuals where TBBPA-sulfate was present in blood, maximum concentrations were obtained at the 4-h sampling point; the concentrations rapidly declined to reach the limit of detection (LOD) after 8 h. Parent TBBPA was not present in detectable concentrations in any of the human plasma samples. TBBPA-glucuronide was slowly eliminated in urine to reach the LOD 124 h after administration. In rats, TBBPA-glucuronide and TBBPA-sulfate were also the major metabolites of TBBPA present in blood; in addition, a diglucuronide of TBBPA, a mixed glucuronide-sulfate conjugate of TBBPA, tribromobisphenol A, and the glucuronide of tribromobisphenol A were also present in low concentrations. TBBPA plasma concentrations peaked at 103 micromol/l 3 h after administration and thereafter declined with a half-life of 13 h; maximal concentrations of TBBPA-glucuronide (25 micromol/l) were also observed 3 h after administration. Peak plasma concentrations of TBBPA-sulfate (694 micromol/l) were reached within 6 h after administration. The obtained results suggest absorption of TBBPA from the gastrointestinal tract and rapid metabolism of the absorbed TBBPA by conjugation resulting in a low systemic bioavailability of TBBPA.     

Effects of fasting and gender on ochratoxin A toxicokinetics in F344 rats

Ochratoxin A (OTA) is a mycotoxin that causes renal tumors in rats, particularly in males. In previous kinetic studies performed in fed conditions (Vettorazzi et al., 2008), mature F344 male rats presented a significantly lower OTA bioavailability than females and young animals. The objective of the present study was to evaluate two factors which could explain this different kinetic profile: the presence of food and the male-specific protein alpha-2u-globulin. Therefore, a 24 h kinetic study has been performed in rats under fasting conditions. Food ingestion has been controlled in both sexes during two months. The presence of alpha-2u-globulin in the urine has been analyzed with SDS-gradient mini-gel electrophoresis.     

Toxicokinetics of chloroethanol in the rat after single oral administration

The excretion and tissue distribution of ¹⁴C-labelled chloroethanol were studied in rats following single oral administration of 5 and 50 mg/kg body weight.At both dose levels, the radioactivity was rapidly eliminated, mainly in the urine. On the first day after application of 5 mg/kg body weight, 77.2% of the dose were found in the urine, 1.7% in the faeces, and 1.0% as carbon dioxide in the expired air. Only 2.8% were excreted by these routes during the following 3 days. The residual radioactivity remaining in the tissues after 4 days was almost equally distributed and amounted to about 0.4% of the dose in the liver and 3% in the whole organism. At the higher dose level, excretion rates and tissue concentrations were similar.Examination of the urine by anion exchange chromatography on DEAE-Sephadex revealed two metabolites which were identified by GC/MS analysis as thiodiacetic acid and thionyldiacetic acid. These metabolites represented almost the whole urinary radioactivity. They were excreted in approximately equal amounts at the low dose whereas the thiodiacetic acid predominated with about 70% of the urinary radioactivity at the high dose. Unchanged chloroethanol, chloroacetic acid, S-carboxymethylcysteine and sulphonyldiacetic acid were not found in the urine.A preliminary report of this study was presented at the 21st Spring Meeting of the Deutsche Pharmakologische Gesellschaft in Mainz, 1980     

Toxicokinetics of Isoeugenol in F344 rats and B6C3F1 mice

Abstract

1. Isoeugenol (IEG) has been tested for toxicity and carcinogenicity due to high potential for human exposure and the structural resemblance to known carcinogenic allylbenzenes. In order to support the interpretation of toxicity and carcinogenecity study outcomes, a toxicokinetic study was performed in which both sexes of F344 rats and B6C3F₁ mice were given IEG as a single intravenous (IV) or gavage administration.

2. Following IV administration, IEG was rapidly eliminated from systemic circulation in both species and sexes. Gavage administration revealed a rapid absorption of IEG with t_max values ≤20?min for both species and sexes. In rats, AUC increased in a greater than dose-proportional manner and Cl_app values decreased with increasing dose in both sexes suggesting saturation of IEG metabolism. On the other hand, Cl_app values in male mice increased with increasing dose suggesting induction of IEG metabolism although this was not evident in the females.

3. Absolute bioavailability was greater in female rats (19%) than male rats (10%) (p?<?0.0001), but was not different between the sexes for mice (28% males; 31% females) (p?=?0.2437). The collective toxicokinetic data supported that low bioavailability following administration of IEG was the result of extensive first-pass metabolism.     

A subchronic toxicity study of Radix Dipsaci water extract by oral administration in F344 rats

Radix Dipsaci, the dried root of Dipsacus asperoides C.Y. Cheng & T.M.Ai, has therapeutic effects on various disorders, and in particular, bone and joint disease. Despite such ethnomedicinal benefits, there is very little information regarding its in vivo toxicity or adverse effects. This study was conducted to evaluate the potential toxicity of the Radix Dipsaci water Extract (RD-wE) by using F344 rats. The RD-wE was administered orally to rats at doses of 0, 125, 250, 500, 1000, and 2000 mg/kg body weight (bw)/day for 13 weeks. During the treatment period there were no mortalities attributed to RD-wE. Moreover, no toxic effects were observed with regard to body weight, clinical pathology (hematology, clinical biochemistry, and urinalysis), and anatomic pathology (gross findings, organ weight, and microscopic examination). The changes related to the treatment were excessive salivation at the mouth and soft feces, observed in male and female rats at 1000 or 2000 mg/kg bw/day, but these were not accompanied by any microscopic correlate or other pathophysiological changes. Based on these results, the oral no-observed-adverse-effect level of the RD-wE was considered to be 2000 mg/kg bw/day in both genders, although the target organs were not determined under the current experimental conditions.     

Kidney and liver distribution of ochratoxin A in male and female F344 rats

The impact of age and gender on Ochratoxin A (OTA) distribution in kidney and liver were studied. OTA was quantified in kidney and liver of young and mature rats of both sexes. Data was fit simultaneously using the population approach with NONMEM program. Fed and fasted mature males showed a 30% decrease and an 11% increase in relative bioavailability, respectively, in comparison with the rest of the groups. The OTA concentrations reached in kidney and liver were very similar between both organs. The models that best fit to data were the ones that considered that distribution of OTA to kidney and liver occurs from the central compartment and that elimination occurs mainly from the liver compartment. The kinetic analysis revealed that both, the apparent volume of distribution of the central compartment (V/F) and the apparent volume of distribution of the liver and kidney compartments (V_L,K/F) increased significantly with body weight. Thus, the sex differences observed in organs distribution are a reflection of the differences in relative bioavailability observed in adult males, as a consequence of the fed and fasted conditions and to the significant higher body weight of mature males which directly affected the V/F and V_L,K/F.     

Subchronic toxicity study of gallic acid by oral administration in F344 rats.

Subchronic toxicity of gallic acid (GA) was investigated in F344 rats by feeding diet containing 0, 0.2, 0.6, 1.7 and 5% GA for 13 weeks. Each group consisted of 10 rats of each sex. Toxicological parameters included clinical signs, body weight, food consumption, hematology, blood biochemistry, organ weights and histopathological assessment. Body weight gain in the 5% GA-treated animals of both sexes from week 1 to the end of the experiment was significantly lower than that of the untreated controls. Toxic effects following administration of 0.6% or more in males and 5% in females included reduction of hemoglobin concentration, hematocrit and red blood cell counts and increase in reticulocytes. Histopathologically, extramedullary hematopoiesis, hemosiderin deposition and congestion appeared in the spleens of 5% GA-treated animals, suggesting development of hemolytic anemia. In addition, centrilobular liver cell hypertrophy, reflected in increase in liver weight, was observed in animals of both sexes from 1.7%. In the kidney, Berlin blue-negative brown pigment deposition in the proximal tubular epithelium was observed at 5% GA. However, the severity of these pathological changes was weak. Based on the present toxicology data, 0.2% was determined to be a no-observed-adverse-effect level (NOAEL) in rats. This level was translated into 119 and 128 mg/kg/day, respectively for male and female rats.     

Toxicokinetics of 4-methylimidazole in the male F344 rat

1. The toxicokinetics and metabolism of 4-methylimidazole (4-MZ) have been studied in the male F344 rat using ¹⁴C radiolabelled compound. Radioactivity in plasma and urine was profiled by hplc.

2. After gavage administration of 50?mg/kg, about 85% of the administered radioactivity was recovered in urine within 48?h. The majority of the radioactivity in urine or plasma was associated with the parent compound and only one minor hydrophilic metabolite was present in urine and in plasma. Elimination of radioactivity via fecal, biliary or respiration was negligible.

3. Elimination of 4-MZ after an i.v. dose of 5mg/kg can be described by a two-compartment process with an estimated half-life of 1.8?h and an estimated apparent volume of distribution of 2.3 litre/kg.

4. After gavage at doses of 5, 50 and 150?mg/kg, 4-MZ was readily absorbed with a estimated bioavailability of 60–70%.

5. Urinary excretion data indicated that renal clearance of 4-MZ accounted for about 80% of total body plasma clearance. Based on the estimated AUC of metabolite and the estimated renal clearance of 4-MZ, the formation of metabolite and the renal clearance of 4-MZ appeared to be a saturable process.     

雷公藤甲素在Beagle犬体内毒代动力学研究

目的：探索性研究雷公藤甲素在犬体内的毒代动力学特征,并观察其毒性反应,为雷公藤甲素毒性机制的深入研究提供研究数据.方法：25只Beagle犬随机分为5组,分别为灌胃给药A组（高剂量,0.1 mg/kg）、B组（中剂量,0.08 mg/kg）、C组（低剂量,0.05mg/kg）,静脉给药D组（0.08 mg/kg）和空白对照组E组,连续给药14d,于给药第1、7和14天采集血样或组织样本供毒代动力学研究及毒性检查（血常规、血生化、病理切片）;14 d给药过程中进行临床症状观察.结果：雷公藤甲素给药后第1天和第14天,静注和口服药代参数均有所变化,静注AUC0-从145.86增加到276.24 ng· h·mL-1,CL从548.45降到301.89mL·h^-1·kg^-1;口服高剂量 AUC0-∞从 151.54 增加到289.98 ng·h·mL^-1,Cmax从44.49增加到75.26 ng/mL;口服中剂量AUC0-∞从37.78增加到61.65 ng· h·mL^-1,Cmax从44.49增加到75.26 ng/mL;口服低剂量AUC0-∞从67.92增加到143.98 ng·h·mL^-1,Cmax从24.05增加到38.07 ng/mL.MRT、T1/2延长.毒性观察结果显示,毒性呈剂量和时间相关性,均出现不同程度的胃肠道反应,肝功能受损,白细胞降低等.结论：本文探索性研究了雷公藤甲素在犬体内的毒代动力学的性质,提示胃肠道和肝脏可能是两个主要的毒性靶器官,同时研究发现给药途径对雷公藤甲素的安全性有较大影响.     

Toxicokinetics and biotransformation of 3-(4-methylbenzylidene)camphor in rats after oral administration

3-(4-Methylbenzylidene)camphor (4-MBC) is an UV-filter frequently used in sunscreens and cosmetics. Equivocal findings in some screening tests for hormonal activity initiated a discussion on a possible weak estrogenicity of 4-MBC. In this study, the toxicokinetics and biotransformation of 4-MBC were characterized in rats after oral administration. Male and female Sprague-Dawley rats (n = 3 per group) were administered single oral doses of 25 or 250 mg/kg bw of 4-MBC in corn oil. Metabolites formed were characterized and the kinetics of elimination for 4-MBC and its metabolites from blood and with urine were determined. Metabolites of 4-MBC were characterized by (1)H NMR and LC-MS/MS as 3-(4-carboxybenzylidene)camphor and as four isomers of 3-(4-carboxybenzylidene)hydroxycamphor containing the hydroxyl group located in the camphor ring system with 3-(4-carboxybenzylidene)-6-hydroxycamphor as the major metabolite. After oral administration of 4-MBC, only very low concentrations of 4-MBC were present in blood and the peak concentrations of 3-(4-carboxybenzylidene)camphor were approximately 500-fold above those of 4-MBC; blood concentrations of 3-(4-carboxybenzylidene)-6-hydroxycamphor were below the limit of detection. Blood concentration of 4-MBC and 3-(4-carboxybenzylidene)camphor peaked within 10 h after 4-MBC administration and then decreased with half-lives of approximately 15 h. No major differences in peak blood levels between male and female rats were seen. In urine, one isomer of 3-(4-carboxybenzylidene)hydroxycamphor was the predominant metabolite [3-(4-carboxybenzylidene)-6-hydroxycamphor], the other isomers and 3-(4-carboxybenzylidene)camphor were only minor metabolites excreted with urine. However, urinary excretion of 4-MBC-metabolites represents only a minor pathway of elimination for 4-MBC, since most of the applied dose was recovered in feces as 3-(4-carboxybenzylidene)camphor and, to a smaller extent, as 3-(4-carboxybenzylidene)-6-hydroxycamphor. Glucuronides of both metabolites were also present in feces, but partly decomposed during sample workup and were thus not quantified. The results show that absorbed 4-MBC undergoes extensive first-pass biotransformation in rat liver resulting in very low blood levels of the parent 4-MBC. Enterohepatic circulation of glucuronides derived from the two major 4-MBC metabolites may explain the slow excretion of 4-MBC metabolites with urine and the small percentage of the administered doses recovered in urine.     

Toxicokinetics of naringin, a putative antitussive, after 184-day repeated oral administration in rats

The toxicokinetic characteristics of naringin were investigated in rats that had been orally administered naringin extract, a candidate for oral treatment of cough, prepared from Citrus grandis "Tomentosa", at 50, 250, or 1250 mg/kg/day in a repeated-dose study for 1, 32, 93, or 184 days. Increased values of the mean systemic exposure were approximately proportional to increases in dose levels during all collection intervals; no saturation was observed. No significant differences in mean systemic exposure were observed between male and female rats. Results provide a reference for interpretation of toxicology findings and relevance to clinical safety issues.     

Toxicokinetics of acrylamide and glycidamide in Fischer 344 rats

Acrylamide (AA) is a widely studied industrial chemical that is neurotoxic, mutagenic to somatic and germ cells, and carcinogenic in rodents. The recent discovery of AA at ppm levels in a wide variety of commonly consumed foods has energized research efforts worldwide to define toxic mechanisms, particularly toxicokinetics and bioavailability. This study compares the toxicokinetics of AA and its epoxide metabolite, glycidamide (GA), in serum and tissues of male and female F344 rats following acute exposure by intravenous, gavage, and dietary routes at 0.1 mg/kg AA or intravenous and gavage routes with an equimolar amount of GA. AA was rapidly absorbed after oral dosing, was widely distributed to tissues, was efficiently converted to GA, and produced increased levels of GA-DNA adducts in liver. GA was also rapidly absorbed, widely distributed to tissues, and produced increased liver DNA adduct levels. AA bioavailability after aqueous gavage was 60--98% and from the diet was 32--44%; however, first-pass metabolism or other kinetic change resulted in much higher internal exposures to GA (2- to 7-fold) when compared to the intravenous route. A similar effect on metabolism to GA following oral administration was previously observed under an identical exposure paradigm in mice. Furthermore, DNA adduct formation in rat liver showed the same proportionality with the respective GA AUC value as did mice in the previous study. These findings suggest that as the AA content in food is reduced, species-differences in GA formation and subsequent DNA adduct formation may be minimized. These findings provide additional information needed to assess genotoxic risks from the low levels of AA that are pervasive in the food supply.     

Toxicokinetics of bisphenol A in female DA/Han rats after a single i.v. and oral administration

Bisphenol A [BPA; 2,2-bis-(4-hydroxyphenyl)-propane] is a monomer used in the manufacture of resins with a wide range of applications, e.g. plastic coatings in the food packaging industry. BPA has been shown to have a weak oestrogenic activity in vitro and in vivo. Despite its low oestrogenic potency there is concern that, as a consequence of slow clearance, BPA might reach biologically significant levels in humans and animals exposed to environmental levels. To address this concern, we assessed the kinetic behaviour of BPA in female DA/Han rats. Groups of female rats received 10 mg BPA/kg body weight intravenously or 10 or 100 mg BPA/kg body weight orally (by gavage). Blood samples were collected at different time-points and plasma was prepared. Free BPA in the samples was isolated by fluid-fluid extraction. BPA was measured by GC-MS which allowed the reliable determination of BPA concentrations as low as approximately 10 ng/ml plasma. Immediately after i.v. administration, the BPA plasma concentration was in the range of about 15 microg/ml and decreased rapidly within the first hour (to 700 ng/ml). The levels declined further (100 ng/ml at 2 h), and after 24 h the analytical detection limit was reached. BPA was detected in plasma as early as 10 min after gavage administration, indicating rapid initial uptake from the gastrointestinal tract. Absorption of BPA was variable. In animals receiving 10 mg/kg, maximal plasma levels were reached after 1.5 h (31 ng/ ml) and 6 h (40 ng/ml). In animals receiving 100 mg/kg, plasma levels reached maxima around 30 min (150 ng/ml) and 3 h (134 ng/ml) after administration. After 48 h BPA was at or below the detection limit in both dose groups. Fluctuations in the BPA plasma concentrations over time point to the possibility of enterohepatic recirculation and protracted absorption from the gastrointestinal tract. Using the area under the concentration-time curves (AUCs), low bioavailabilities of 16.4% and 5.6% were calculated for the 10 and 100 mg/kg dose groups, respectively. The toxicokinetic properties of BPA in DA/Han rats are in agreement with the hypothesis of a rapid first-pass elimination by the liver and efficient metabolic clearance of low oral doses. Only excessive doses may lead to bioaccumulation if detoxification pathways are saturated.     

Metabolism and disposition of hydroquinone in Fischer 344 rats after oral or dermal administration.

Studies were conducted to determine the absorption, tissue distribution, excretion, and metabolism of 14C-hydroquinone (HQ) in male and female rats following single oral, repeated oral, or 24-h dermal administration. The concentration of parent compound in blood was also determined following a single 50-mg/kg gavage administration. Absorption into the blood was rapid after oral dosing; the maximum concentration of parent compound was attained within 20 min after dosing, and the maximum concentration of total 14C was attained within 30 min. Parent compound represented 1% of total 14C in blood, indicative of extensive first-pass metabolism. Excretion was primarily via the urine within the first 8h of gavage. Typically, 87-94% of the 14C was excreted in urine. Dermal application of 14C-HQ (20 microCi) as a 5.4% aqueous solution resulted in near background levels of 14C in blood; the maximum mean blood concentration was 0.65 microg HQ equivalents/g in females and not quantifiable in males. The majority (61-71%) of the 14C was recovered from the skin surface by washing at 24 h. HQ was extensively metabolized following oral dosing with typically <3% of the dose excreted as parent compound. The major urinary metabolites of HQ were glucuronide and O-sulfate conjugates, which represented 45-53% and 19-33%, respectively, of an oral dose. A <5% metabolite was identified as a mercapturic acid conjugate of HQ.     

The role of alpha2u-globulin in ochratoxin A induced renal toxicity and tumors in F344 rats

The mycotoxin ochratoxin A (OTA) was shown to be a potent kidney carcinogen in rats demonstrating a marked sex difference in the response. Compared to female rats, male rats had a 10-fold higher incidence of kidney carcinomas. The objective of this study was to investigate whether this sex difference in tumor response is due to an exacerbation of effect resulting from the interaction of the male rat specific urinary protein alpha2u-globulin (alpha2u) with OTA. Male and female rats were treated by oral gavage with OTA (1 mg/kg per day), D-limonene (dL; 1650 mg/kg per day) as a positive control or corn oil for 7 consecutive days. OTA induced severe renal lesions predominantly in the P3 region of the proximal tubules. The lesions consisted of necrotic cells and cell exfoliations. No hyaline droplets were found in the P2 segment following OTA treatment, whereas dL induced the expected accumulation of droplets. The results suggest that OTA induced kidney lesions are in all characteristic points different from the known alpha2u-nephropathy induced by dL. Based on these experiments the male rat specific protein alpha2u does not seem to be involved in the mechanism(s) leading to the high tumor incidence observed in OTA exposed male rats.