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Biomedical subjects

J G Dent

Publications and source records attributed to J G Dent.

At least 37 records · Page 2Linked to original sources
PubMed1981

alpha-Naphthylisothiocyanate induced alterations in hepatic drug metabolizing enzymes and liver morphology: implications concerning anticarcinogenesis.

Alpha-naphthylisothiocyanate (ANIT) is a biliary toxin with anticarcinogenic properties. The studies described were designed to investigate the effects of continuous ANIT feeding on liver function. Male F-344 rats were fed ANIT at 0.01%, 0.022%, 0.047%, and 0.1% of the diet for 2, 4, and 6 weeks. Microscopic evaluation of liver sections revealed time- and dose- dependent bile duct proliferation, bile duct cell hypertrophy, and focal hepatocytic necrosis. Liver derived serum enzyme activity and serum bilirubin concentrations were increased in a fashion which correlated closely with the histological observations. A dose dependent decrease in hepatic cytochrome P-450 content, ethoxycoumarin-O-deethylase activity, and benzphetamine-N-demethylase activity was observed after 2 and 4 weeks of feeding ANIT. However, these enzyme activities returned to control values at 6 weeks in all except the 0.1% group. ANIT increased microsomal epoxide hydrolase and cytosolic DT-diaphorase activity (200-6005 of control). The enhancement was dose related and peaked at 2 and 4 weeks for epoxide hydrolase and DT-diaphorase, respectively. Both epoxide hydrolase and DT-diaphorase activity remained elevated at 6 weeks. These results suggest that ANIT mediated anticarcinogenesis, previously hypothesized to be the result of reduced mixed function oxidase activity, also may be accounted for by enhanced epoxide hydrolase and DT-diaphorase activity.

1-Naphthylisothiocyanate↗
PubMed1981

Sex-dependent metabolism and biliary excretion of [2,4-14C] dinitrotoluene in isolated perfused rat livers.

The incidence of hepatocellular carcinoma is higher in male rats fed 35 mg of dinitrotoluene (DNT) per kg than in female rats fed the same dose. Sex differences in DNT disposition and/or metabolism may account for this difference. This study characterized the metabolism and biliary excretion of 2,4-DNT in male and female isolated perfused rat livers. Livers from both sexes displayed a capacity for oxidation, reduction, acetylation and conjugation of 2,4-DNT (or its metabolites). Oxidation of 2,4-DNT to 2,4-dinitrobenzyl alcohol followed by glucuronidation to 2,4-dinitrobenzyl alcohol glucuronide (DNBalcG) was the major route of 2,4-DNT metabolism in both sexes. Formation of DNBalcG accounted for 10 to 30% of the total initial 2,4-DNT concentration in perfusates. After perfusion with 20 microM 2,4-DNT, male livers excreted larger quantities of DNBalcG in the bile (392 nmol) than female livers (172 nmol); at the same 2,4-DNT concentration, perfusates from female livers contained over 3 times as much DNBalcG as male perfusates. These data suggested that female livers transported DNBalcG into the bile at slower rates than male livers. The transport of DNBalcG into the bile of male, but not female, livers appeared to be saturated after perfusion with 20 micro M 2,4-DNT. No sex differences in the hepatic macromolecular covalent binding were observed after perfusion of livers with either 20 or 70 micro M 2,4-DNT. These data suggest that the major difference in the in vitro metabolism of 2,4-DNT between male and female rats is the larger quantities of DNBalcG excreted in the bile of male rats than female rats.

Animals↗
PubMed1980

A new method for measuring covalent binding of chemicals to cellular macromolecules.

A new method has been developed for measuring the total covalent binding of metabolically activated compounds to cellular macromolecules. This method employs equilibrium dialysis, in the presence of the detergent sodium dodecyl sulfate (SDS), to remove unbound radiolabeled compound and its metabolites from cellular macromolecules. [14C] Bromobenzene (80 microM), [14C]aflatoxin B1 (5 microM) or 3-[14C]methylcholanthrene (100 microM) was incubated (37 degrees C) with primary hepatocytes or liver microsomes isolated from Fischer-344 rats. The covalent binding of 14C-radiolabel to hepatic or microsomal macromolecules was measured by SDS-equilibrium dialysis and compared with that measured by exhaustive extraction. After 1 h of incubation with hepatocytes or microsomes, 2--7 times more covalent binding was detected by SDS-equilibrium dialysis, than by exhaustive extraction. The radioactivity associated with these hepatic or microsomal macromolecules migrated to discrete positions on SDS-polyacrylamide disc gels. The non-dialysable radioactivity from incubations with [14C] bromobenzene could not be extracted with diethyl ether even after treatment of the dialysin with beta-glucuronidase-sulfatase or dilute acid. This was taken to indicate that the radioactivity in the dialysin did not include free bromobenzene or its metabolites, a conclusion supported by thin-layer chromatography analysis of the dialysin. The lower amount of covalent binding detected by exhaustive extraction may be related to the inability of trichloroacetic acid to quantitatively precipitate small molecular weight macromolecules. SDS-equilibrium dialysis is an easy, rapid and non-destructive technique for measuring covalent binding. The macromolecular integrity of the sample is maintained and allows further studies concerning the specificity of the covalent interactions.

Aflatoxins↗
PubMed1979

Effect of polybrominated biphenyls on the development of hepatic excretory function.

Polybrominated biphenyls (PBBs) stimulate hepatic drug metabolism in adult and developing rats. The purpose of this investigation was to determine the influence of PBBs on the development of the liver as an organ for chemical excretion. Exposure of developing rats to polybrominated biphenyls (PBBs) by feeding 50 ppm of PBBs to pregnant or lactating mothers and rat weanlings did not produce overt toxicity when compared to controls over a 49-day postnatal period. However, prenatal and postnatal dietary exposure to PBBs resulted in elevated liver weight. In 15-day-old rats, increased liver weight after PBBs was correlated with enhanced ouabain transport from plasma into bile. Liver weight was also elevated in 21-, 35- and 49-day-old rats treated with PBBs, but this effect was not associated with stimulation of ouabain transport in these animals. Stimulation of ouabain transport after PBBs in 15-day-old rats was associated with increased hepatic uptake of ouabain. Stimulation in 15-day-old rats and not older rats may be attributed to the relative importance of uptake for ouabain transport in 15-day-old rats.

Aging↗
PubMed1978

Characteristics of cytochrome P-450 and mixed function oxidase enzymes following treatment with PBBs.

The mixture of PBBs in FireMaster BP-6 has been demonstrated to constitute potent inducers of hepatic and extrahepatic mixed function oxidase (MFO) enzymes. Chronic dietary administration of PBBs to mature female rats results in a "mixed" pattern of induction, with increases in both cytochrome P-450 and P1-450 associated enzymes. Acute administration of PBBs (150 mg/kg IP) to mature female rats resulted in a time-dependent induction of MFO activities; the P-450-dependent enzymes were simulated early (24-48 hr after administration) while the P1-450 dependent enzymes reached maximal activities at later time points. However, studies of the kinetics and patterns of inhibition of the induced enzymes along with gel electrophoresis studies of the microsomal proteins indicate that PBBs may induce different proteins from those induced by the classical P-450 and P1-450 inducers, phenobarbital and 3-methylcholanthrene. In addition, the pattern of enzyme induction caused by PBBs in developing rats differs from that in adults, in that the P1-450-associated enzymes are stimulated prior to the P-450-associated enzymes. The overall pattern of enzyme induction in extrahepatic tissue differs from that seen in the liver and sex differences in enzyme induction have also been demonstrated. As modifications of MFO activity may alter the toxicity of chemicals, these findings suggest that the toxicity of chemicals may be altered in animals exposed to PBBs and that these toxicities may exhibit age, sex, and organ specificities different from those seen in control animals.

Animals↗
PubMed1978

Distribution of polybrominated biphenyls after dietary exposure in pregnant and lactating rats and their offspring.

Female rats were fed PBBs in the diet (50 ppm) from day 8 of gestation to day 21 of gestation, from day 1 postpartum to day 14 postpartum or from day 8 of gestation through day 14 postpartum. Levels of PBBs were measured in various tissues. Small concentrations of PBBs (less than 5 microgram/g) were found in the brain, heart, lung, liver, small intestine, placenta, and gravid uterus. Larger concentrations (less than 30 microgram/g) were found in kidneys, the nongravid uterus, skin, mammary tissue, and fat. Lactation did not significantly alter the concentrations of PBBs found in tissues other than mammary tissue. Offspring were subjected to several exposure regimens by cross-fostering. Concentrations of PBBs in the neonatal livers were higher than in the adults nursing them. Transfer of PBBs via the milk appears to be much more important to appearance of PBBs in newborns than does placental transfer.

Animal Feed↗
PubMed1977

Stimulation of hepatic microsomal metabolism in mice by a mixture of polybrominated biphenyls.

The pattern of stimulation of hepatic microsomal mixed function oxidases has been studied in female NMRI mice following a single ip injection of 150 mg/kg polybrominated biphenyls (PBBs) and compared to the patterns produced by phenobarbital (PB), 3 X 100 mg/kg; 3-methylcholanthrene (MC), 3 X 20 mg/kg; and these two agents administered together at these doses. Cytochrome P450, ethylmorphine N-demethylase, and epoxide hydratase reached maximums of 200, 200, and 350% of control values, respectively, at 48 hr after treatment with PBBs. Ethoxycoumarin O-deethylase and arylhydrocarbon hydroxylase were maximally increased to 400 and 180% of control values, respectively, 96 hr after PBBs. The reduced cytochrome P450 ethylisocyanide difference spectra and the inhibition of ethoxycoumarin O-deethylase and arylhydrocarbon hydroxylase activity by metyrapone and alpha-naphthoflavone indicated that the characteristics of the cytochrome P450 and the cytochrome P450-dependent enzymes changed with time after administration of PBBs. These results indicate that the enzyme-stimulating properties of PBBs alter, changing from PB-like to MC-like, with time after administration. These findings provide an explanation for the effects of PBBs on the toxicity of bromobenzene, indicating that PBBs represent a new and previously unrecognized calss of toxicity-modifying agents sharing properties of both PB and MC.

Animals↗