Inhibition of catalase-dependent ethanol metabolism in alcohol dehydrogenase-deficient deermice by fructose.
Hepatic microsomal fractions from ADH (alcohol dehydrogenase)-negative deermice incubated with an NADPH-generating system metabolized butanol and ethanol at rates around 10 nmol/min per mg. In contrast, cytosolic catalase from ADH-negative deermouse liver oxidized ethanol, but not butanol, when incubated with an H2O2-generating system. Thus butanol is oxidized by cytochrome P-450 in microsomal fractions, but not by cytosolic catalase, in tissues from ADH-negative deermice. In perfused livers from ADH-negative deermice, rates of ethanol uptake at low concentrations of ethanol (1.5 mM) were about 60 mumol/h per g, yet butanol (1.5 mM) uptake was undetectable (less than 4 mumol/h per g). At higher concentrations of alcohol (25-30 mM), rates of ethanol uptake were about 80 mumol/h per g, whereas rates of butanol uptake were only about 9 mumol/h per g. Because rates of butanol metabolism via cytochrome P-450 in deermice were more than an order of magnitude lower than rates of ethanol uptake in livers from ADH-negative deermice, it is concluded that ethanol uptake by perfused livers from ADH-negative deermice is catalysed predominantly via catalase-H2O2. In support of this conclusion, rates of H2O2 generation, which are rate-limiting for the peroxidation of ethanol by catalase, were about 65 mumol/h per g in livers from ADH-negative deermice, values similar to rates of ethanol uptake of about 60 mumol/h per g measured under identical conditions. Rates of ethanol uptake by perfused livers from ADH-positive, but not from ADH-negative, deermice were increased by about 50% by infusion of fructose. Thus it is concluded that the stimulation of hepatic ethanol uptake by fructose is dependent on the presence of ADH. Unexpectedly, fructose decreased rates of ethanol metabolism and H2O2 generation by about 60% in perfused livers from ADH-negative deermice, probably by decreasing activation of fatty acids and thus diminishing rates of peroxisomal beta-oxidation.
Handler
J A
JA
Department of Pharmacology, University of North Carolina, Chapel Hill 27514.
Bradford
B U
BU
Glassman
E B
EB
Forman
D T
DT
Thurman
R G
RG
D000426:Alcohol Dehydrogenase / Q000172:deficiency*; D000818:Animals; D000440:Butanols / Q000378:metabolism; D002374:Catalase / Q000378:metabolism*; D000431:Ethanol / Q000378:metabolism*; D005260:Female; D005632:Fructose / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D010542:Peromyscus
D000440:Butanols; D005632:Fructose; D000431:Ethanol; D006861:Hydrogen Peroxide; D000426:Alcohol Dehydrogenase; D002374:Catalase