Synergistic induction of monooxygenase activity by glucocorticoids and polycyclic aromatic hydrocarbons in human fetal hepatocytes in primary monolayer culture.
The ability of polycyclic aromatic hydrocarbons and glucocorticoids to regulate monooxygenase activity of human fetal liver has been studied using hepatocytes prepared by collagenase digestion of liver samples from human abortuses of 13 to 19 weeks of gestational age, and maintained in primary monolayer culture for periods up to 5 days. Addition of 1,2-benzanthracene to the cells caused an increase in monooxygenase activity (3-hydroxylation of benzo[a]pyrene and O-deethylation of 7-ethoxycoumarin) in a time-and concentration-dependent fashion. The concentration of 1,2-benzanthracene required to achieve half-maximal induction was 5 microM. The inductive effect of the polycyclic hydrocarbon was potentiated approximately 2.5-fold when dexamethasone (250 nM) or other glucocorticoids were included in the culture medium. Dexamethasone alone had little or no effect on the induction of monooxygenase activity. The concentration of dexamethasone required for half-maximal stimulation of monooxygenase activity in the presence of 1,2-benzanthracene was 5-10 nM, and the action of dexamethasone was reversed by the addition of cortisol 21-mesylate, consistent with the concept that the action of dexamethasone was mediated by binding to a glucocorticoid receptor. These results are suggestive that glucocorticoids, which are produced by the fetal adrenal and have an important role in the regulation of fetal development, act synergistically with polycyclic aromatic hydrocarbons to induce the activity of liver monooxygenases in the human fetus.
D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D001551:Benz(a)Anthracenes / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000378:metabolism; D002478:Cells, Cultured; D003374:Coumarins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000201:enzymology*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000494:pharmacology; D006900:Hydroxylation; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D010105:Oxygenases / Q000096:biosynthesis*; D011083:Polycyclic Compounds / Q000494:pharmacology*; D011247:Pregnancy; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000187:drug effects
D001551:Benz(a)Anthracenes; D003374:Coumarins; D005938:Glucocorticoids; D011083:Polycyclic Compounds; D011965:Receptors, Glucocorticoid; D011285:Pregnenolone Carbonitrile; C017299:7-ethoxycoumarin; D001564:Benzo(a)pyrene; C027504:cortisol 21-mesylate; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; C030935:benz(a)anthracene; D010105:Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; D006854:Hydrocortisone