title: Effect of propylthiouracil treatment on NADPH-cytochrome P450 reductase levels, oxygen consumption and hydroxyl radical formation in liver microsomes from rats fed ethanol or acetone chronically.
abstract: The antithyroid drug propylthiouracil (PTU) has been shown previously to reduce hepatic oxygen utilization and to protect the liver from ethanol-induced injury. The present study examined the effect of PTU on hepatic microsomal oxygen consumption and on the activities of NADPH-cytochrome P450 reductase (CYP-reductase) and cytochrome P4502E1 (CYP2E1) in rats receiving ethanol or acetone chronically. Liver microsomes from rats treated with ethanol for 29 days displayed increases in (i) O2 consumption (70%), (ii) hydroxyl radical (.OH) production (49%) and (iii) ethanol oxidation (50%). Microsomal CYP2E1 levels were increased markedly by chronic ethanol administration, while CYP-reductase was affected marginally, but not significantly (P = 0.06). Chronic treatment with acetone for 14 days, produced similar effects, except that .OH production was not enhanced. Administration of PTU (25 mg/kg/day) to ethanol- or acetone-fed rats, for 10 and 14 days, respectively, led to a marked reduction in the levels and activity of CYP-reductase, and to a decrease in the rates of microsomal O2 consumption, .OH production and ethanol oxidation, but did not lower the levels of CYP2E1 or the metabolism of the CYP2E1 substrate N,N-nitrosodimethylamine. These data suggest that the ability of PTU to protect the liver from ethanol-induced injury may be due to a reduction in the levels of CYP-reductase, thereby minimizing the enhancement of microsomal oxygen consumption and free radical generation associated with ethanol-induced CYP2E1 activity.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Toronto, Ontario, Canada.
authors.forename: A D
authors.initials: AD
authors.lastname: Ross
authors.forename: G
authors.initials: G
authors.lastname: Varghese
authors.forename: B
authors.initials: B
authors.lastname: Oporto
authors.forename: F J
authors.initials: FJ
authors.lastname: Carmichael
authors.forename: Y
authors.initials: Y
authors.lastname: Israel
mesh_terms: D000096:Acetone / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D017665:Hydroxyl Radical / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology*; D009251:NADPH-Ferrihemoprotein Reductase; D010088:Oxidoreductases / Q000096:biosynthesis*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D010101:Oxygen Consumption; D011441:Propylthiouracil / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013963:Thyroid Hormones / Q000097:blood
chemical_list: D013963:Thyroid Hormones; D000096:Acetone; D017665:Hydroxyl Radical; D000431:Ethanol; D011441:Propylthiouracil; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D009251:NADPH-Ferrihemoprotein Reductase