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.
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.
Ross
A D
AD
Department of Pharmacology, Faculty of Medicine, University of Toronto, Ontario, Canada.
Varghese
G
G
Oporto
B
B
Carmichael
F J
FJ
Israel
Y
Y
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
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