TY - JOUR
T1 - Differential effects of chronic ethanol feeding on cytochrome P-448- and P-450-mediated drug metabolism in the rat
AU - Mltchell, Mack C.
AU - Hoyumpa, Anastacio
AU - Schenker, Steven
AU - Patwardhan, Rashmi V.
N1 - Funding Information:
* Supported by the Veterans Administration Research Service &d NIH-Grants AA 00267-11 and AA 04860-01. t This work was nublished in abstract form TM. C. Mitchell, A. Hoyumpa, S. Schenker and R. V.*Patwardhan, Gu~troenterotogy 80, 1342 (19gl)J. $ Dr. Mitchell is the recipient of a National Institutes of Health Individual Research Fellowship Award and an American Liver Foundation Research Fellowship Award. g Address correspondence to: Mack C. Mitchell, M.D., VA Medical Center, Rm B-230,1310 24th Avenue, South, Nashville, TN 37203, U.S.A.
PY - 1982/3/1
Y1 - 1982/3/1
N2 - The effects of chronic ethanol feeding on cytochrome P-448- and P-450-mediated drug metabolism have been studied both in vivo and in vitro in the rat, using caffeine, phenacetin, antipyrine and aminopyrine as test substrates. N-Demethylation of aminopyrine (P-450 mediated) was increased both in vivo and in vitro in rats after chronic ethanol feeding (P < 0.05) whereas in vivo N-demethylation of caffeine and O-dealkylation of phenacetin (P-448 mediated) were unchanged in the same animals. N-rmDemethylation of antipyrine was increased by both phenobarbital and 3-methylcholanthrene pretreatment and by chronic ethanol feeding (P < 0.05), possibly due to cytochrome P-450 induction. Furthermore, the Michaelis affinity constants. Km, for hepatic microsomal aminopyrine N-demethylase and antipyrine N-demethylase were lower in chronic ethanol-fed animals (P < 0.05), suggesting a qualitative change in the enzymes resulting in greater substrate affinity. These findings suggest a differential effect of chronic ethanol feeding on the induction of cytochrome P-450- and cytochrome P-448-mediated drug metabolism, with a greater effect on the former microsomal system.
AB - The effects of chronic ethanol feeding on cytochrome P-448- and P-450-mediated drug metabolism have been studied both in vivo and in vitro in the rat, using caffeine, phenacetin, antipyrine and aminopyrine as test substrates. N-Demethylation of aminopyrine (P-450 mediated) was increased both in vivo and in vitro in rats after chronic ethanol feeding (P < 0.05) whereas in vivo N-demethylation of caffeine and O-dealkylation of phenacetin (P-448 mediated) were unchanged in the same animals. N-rmDemethylation of antipyrine was increased by both phenobarbital and 3-methylcholanthrene pretreatment and by chronic ethanol feeding (P < 0.05), possibly due to cytochrome P-450 induction. Furthermore, the Michaelis affinity constants. Km, for hepatic microsomal aminopyrine N-demethylase and antipyrine N-demethylase were lower in chronic ethanol-fed animals (P < 0.05), suggesting a qualitative change in the enzymes resulting in greater substrate affinity. These findings suggest a differential effect of chronic ethanol feeding on the induction of cytochrome P-450- and cytochrome P-448-mediated drug metabolism, with a greater effect on the former microsomal system.
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U2 - 10.1016/0006-2952(82)90452-X
DO - 10.1016/0006-2952(82)90452-X
M3 - Article
C2 - 7082337
AN - SCOPUS:0019945779
SN - 0006-2952
VL - 31
SP - 695
EP - 699
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 5
ER -