Comparative induction of xenobiotic metabolism in rodent kidney, testis and liver by commercial mixtures of polybrominated biphenyls and polychlorinated biphenyls, phenobarbital and 3-methylcholanthrene: absolute and temporal effects.
Male Fischer 344 rats were killed at various times after single or multiple treatments with polybrominated biphenyls (PBB), polychlorinated biphenyls (PCB), sodium phenobarbital (NaPB) or 3-methylcholanthrene (3MC). p-Chloro-N-methyl-aniline N-demethylase (PCNMA) and aryl hydrocarbon hydroxylase (AHH) activities were determined in the 14 000 g supernatant fraction (postmitochondrial supernate, PMS) of renal, testicular and hepatic homogenates. Cytochrome P-450 (p-450) concentrations were determined in the 100 000 g pellet fractions of the same homogenates and the effects of enzyme induction on the sensitivities of AHH in PMS to inhibition by alpha-napthoflavone (ANF) and metyrapone (MET) in vitro were determined. Single treatments with PBB or PCB induced hepatic P-450 only, while multiple treatments with PBB, PCB or 3MC induced both renal and hepatic P-450; NaPB induced only hepatic P-450, while testicular P-450 concentration was unaffected by the inducers. Treatments with PBB, PCB or 3MC shifted the Soret maxima of renal and hepatic dithionite-reduced P-450 difference spectra to shorter wavelengths. Multiple treatments with PBB, PCB or 3MC increased renal and hepatic AHH activities, but NaPB induced hepatic AHH only. Renal AHH activity was increased more rapidly than hepatic AHH after a single treatment with PBB, PCB or 3MC and returned more rapidly to control. The renal AHH induced by PBB and PCB, like that induced by 3MC, was more sensitive to inhibition by ANF in vitro than was renal AHH from naive rats. Hepatic AHH induced by PBB and PCB, unlike that induced by NaPB or 3MC, exhibited no net alterations in sensitivities to the inhibitory effects of ANF or MET. Testicular AHH activity was not induced by PBB, PCB , NaPB or 3MC. Multiple treatments with PBB, PCB or NaPB increased hepatic, but not renal or testicular PCNMA activities. The organ-specificity and time-dependency of the effects of PBB, PCB, NaPB and 3MC on P-450 concentrations and AHH activities suggest that drug metabolism in kidney, testis and liver are regulated by separate control mechanisms. It may be possible to exploit such differences in organ response to enzyme inducers as tools with which to discern the roles of local metabolism in renal and testicular chemical injury.
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000187:drug effects; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology*; D011075:Polybrominated Biphenyls / Q000494:pharmacology*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013737:Testis / Q000378:metabolism; D013997:Time Factors
D001713:Biphenyl Compounds; D004364:Pharmaceutical Preparations; D011075:Polybrominated Biphenyls; D008748:Methylcholanthrene; D011078:Polychlorinated Biphenyls; D010634:Phenobarbital