Synergistic induction of cytochrome P450 by ethanol and isopentanol in cultures of chick embryo and rat hepatocytes.
The purpose of this study was to investigate whether isopentanol, the most abundant higher chain alcohol in alcoholic beverages, contributes to induction of different forms of hepatic P450s associated with consumption of these beverages. We have previously reported that ethanol and isopentanol each induce P450 2H1/2 in cultured chick hepatocytes and that ethanol induced P450 2B1/2, as well as P450 2E, in cultured rat hepatocytes. Here we investigated the induction of P450 by isopentanol alone and in combination with ethanol in cultured chick and rat hepatocytes. The forms of induced P450 were identified both enzymatically and immunochemically. In cultured chick hepatocytes, both isopentanol and ethanol induced P450 2E, but combined treatment with these alcohols had no greater effect than treatment with ethanol alone. In cultured rat hepatocytes, isopentanol alone did not induce P450 2E or 2B1/2 and had no effect on the ethanol-mediated induction of P450 2E. However, isopentanol combined with ethanol caused a synergistic induction of P450 2B1/2 in cultured rat hepatocytes and an additive to synergistic induction of P450 2H1/2 in cultured chick hepatocytes. The levels of enzyme activities induced by the combined alcohol treatment approached those induced by potent barbiturates. The results suggest that the pentanols in alcoholic beverages may be responsible for a barbiturate-like induction of P450 in hepatocytes.
Louis
C A
CA
Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire 03756.
Sinclair
J F
JF
Wood
S G
SG
Lambrecht
L K
LK
Sinclair
P R
PR
Smith
E L
EL
D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D019362:Cytochrome P-450 CYP2B1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D000439:Pentanols / Q000494:pharmacology*; D051381:Rats
D000439:Pentanols; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; C029683:isopentyl alcohol; D010088:Oxidoreductases; D019362:Cytochrome P-450 CYP2B1; C019781:benzphetamine N-demethylase; D010089:Oxidoreductases, N-Demethylating