Ethanol and isopentanol increase CYP3A and CYP2E in primary cultures of human hepatocytes.
In primary cultures of human hepatocytes prepared from three separate livers, ethanol increased both CYP3A and CYP2E1, as detected immunochemically. Isopentanol, the major higher chain alcohol in alcoholic beverages, also induced CYP3A and CYP2E1. Maximal increases in these P450s occurred at the lowest concentrations of isopentanol examined, 0.1 mM. Ethanol and isopentanol were each more potent and more effective at inducing CYP3A in the human hepatocytes than was previously shown in cultured rat hepatocytes. Steady-state levels of CYP3A3/4 mRNA were increased by both ethanol and isopentanol. Ethanol and isopentanol induced immunoreactive CYP3A to a greater extent than did phenobarbital. In all three cultures, the increases in CYP3A after treatment with ethanol were less than those observed after treatment with rifampicin, a highly effective inducer of CYP3A in human hepatocytes. In one human hepatocyte culture, the lowest concentration of isopentanol tested increased CYP3A protein to an amount similar to that increased by rifampicin. In another human hepatocyte culture, however, the amount of immunoreactive CYP3A increased by isopentanol was less than that increased by rifampicin. In this latter culture, the steady-state levels of CYP3A3/4 mRNA increased by 0.1 mM isopentanol and 1 microM rifampicin were similar. This is the first finding of induction of CYP3A in human hepatocytes by ethanol or isopentanol. The clinical significance of the findings is discussed.
Kostrubsky
V E
VE
Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire 03056, USA.
Strom
S C
SC
Wood
S G
SG
Wrighton
S A
SA
Sinclair
P R
PR
Sinclair
J F
JF
D000293:Adolescent; D000328:Adult; D000428:Alcohol Drinking / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D000439:Pentanols / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D012293:Rifampin / Q000494:pharmacology
D000439:Pentanols; D012333:RNA, Messenger; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; C029683:isopentyl alcohol; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D012293:Rifampin; D010634:Phenobarbital