Effects of the interferon inducing agents tilorone and polyriboinosinic acid . polyribocytidylic acid (poly IC) on the hepatic monooxygenase systems of pregnant and fetal rats.
Interferon inducing agents, including tilorone and polyriboinosinic acid . polyribocytidylic acid (poly IC), are known to depress hepatic cytochrome P-450-dependent monooxygenase systems and the induction of these systems by phenobarbital (PB) and 3-methylcholanthrene (MC) in mature male rats. The current study investigated the effects of tilorone and poly IC on the cytochrome P-450 systems of non-induced, PB-induced, MC-induced and pregnenolonecarbonitrile (PCN)-induced pregnant rats and their fetuses. Pregnant rats received either tilorone or poly IC and saline, PB, MC or PCN, and microsomes from their livers and those of their fetuses were examined for cytochrome P-450 content, aminopyrine (AP) N-demethylase activity and benzo[a]pyrene (BP) hydroxylase activity. The generalization can be made from these studies that, when the interferon inducing agents caused changes in cytochrome P-450 content or monooxygenase activities of either induced (PB, MC or PCN) or non-induced (saline) animals, decreases were seen in maternal livers and increases in fetal livers. Thus, in maternal livers tilorone depressed cytochrome P-450 and AP N-demethylase activity in non-induced and PB-, MC- and PCN-induced rats and BP hydroxylase activity in the induced animals; BP hydroxylase activity was not depressed in non-induced maternal livers. Poly IC depressed cytochrome P-450 and AP N-demethylase activity in non-induced and PB-induced rats but not in PCN-induced animals. BP hydroxylase was depressed by poly IC in both PB- and PCN-induced animals. Fetal hepatic cytochrome P-450 and monooxygenase activities were increased by tilorone in PB- and PCN-induced rats but not in non-induced or MC-induced animals. Poly IC increased cytochrome P-450 and both monooxygenase activities in PB- and PCN-induced fetal livers, whereas only BP hydroxylase activity was increased in the fetuses of non-induced rats. Several possible explanations are offered for the opposite effects produced by interferon inducing agents in maternal and fetal livers. Unlike maternally administered tilorone, which induced fetal cytochrome P-450 and monooxygenase activities in the liver, intrauterine tilorone depressed cytochrome P-450 and had no effect on AP N-demethylase or BP hydroxylase activities in the fetal liver. Intrauterine poly IC was without effect on the cytochrome P-450 systems of the fetal liver. Treatment of pregnant rats with tilorone on days 17-20 of gestation inhibited normal maternal weight gain and produced overt signs of toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)
D000633:Aminopyrine N-Demethylase / Q000037:antagonists & inhibitors; D000818:Animals; D001579:Benzopyrene Hydroxylase / Q000037:antagonists & inhibitors; D003577:Cytochrome P-450 Enzyme System; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000201:enzymology; D005449:Fluorenes / Q000494:pharmacology*; D008099:Liver / Q000196:embryology / Q000201:enzymology*; D008431:Maternal-Fetal Exchange; D008748:Methylcholanthrene / Q000494:pharmacology; D010105:Oxygenases / Q000037:antagonists & inhibitors*; D010634:Phenobarbital / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology*; D011247:Pregnancy; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013994:Tilorone / Q000494:pharmacology*
D005449:Fluorenes; D011285:Pregnenolone Carbonitrile; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D001579:Benzopyrene Hydroxylase; D000633:Aminopyrine N-Demethylase; D013994:Tilorone; D011070:Poly I-C; D010634:Phenobarbital