Synergistic increases in rat hepatic cytochrome P450s by ethanol and isopentanol.
The purpose of this study was to determine if isopentanol alone or in combination with ethanol increased CYP2B1/2, CYP2E or CYP3A in the livers of rats. Increasing doses of isopentanol (0.5, 1, 2 or 3%) were administered in combination with 5.6% ethanol in the Lieber-DeCarli liquid diet for 7 days. Doses of 0.5 or 3% isopentanol were also administered alone. Isopentanol alone caused small increases in CYP2B1/2 and CYP3A. However, when isopentanol (2 or 3%) was combined with ethanol a synergistic increase in P4502B1/2 was observed. The combined alcohol treatment also resulted in a greater increase in immunoreactive CYP3A than either alcohol alone. Ethanol alone increased CYP2E 5-fold. Inclusion of isopentanol with ethanol resulted in either small or no additional increases in CYP2E. These results confirm our previous findings in cultured hepatocytes that when isopentanol is combined with ethanol, there is a synergistic increase in CYP2B1/2. Increases in CYP2B1/2, CYP2E and CYP3A protein moieties by ethanol, and by ethanol in combination with isopentanol, were associated with increases in their mRNAs. Blood isopentanol levels were 10-fold greater in rats administered 3% isopentanol in combination with ethanol compared to rats administered 3% isopentanol alone. From these results we suggest that isopentanol, a higher chain alcohol in alcoholic beverages, can contribute to increases in hepatic cytochrome P450 observed following consumption of alcoholic beverages.
Louis
C A
CA
Veterans Administration Medical Center, White River Junction, Vermont.
Wood
S G
SG
Kostrubsky
V
V
Sinclair
P R
PR
Sinclair
J F
JF
D000818:Animals; D001483:Base Sequence; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004357:Drug Synergism; D004789:Enzyme Activation; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008969:Molecular Sequence Data; D000439:Pentanols / Q000097:blood / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D000439:Pentanols; D012333:RNA, Messenger; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; C029683:isopentyl alcohol