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Abstract
The apparent deuterium isotope effects on Vmax/Km (D(V/K] of ethanol oxidation in two deermouse strains (one having and one lacking hepatic alcohol dehydrogenase (ADH] were used to calculate flux through the ADH, microsomal ethanol-oxidizing system (MEOS), and catalase pathways. In vitro, D(V/K) values were 3.22 for ADH, 1.13 for MEOS, and 1.83 for catalase under physiological conditions of pH, temperature, and ionic strength. In vivo, in deermice lacking ADH (ADH-), D(V/K) was 1.20 +/- 0.09 (mean +/- S.E.) at 7.0 +/- 0.5 mM blood ethanol and 1.08 +/- 0.10 at 57.8 +/- 10.2 mM blood ethanol, consistent with ethanol oxidation principally by MEOS. Pretreatment of ADH- animals with the catalase inhibitor 3-amino-1,2,4-triazole did not significantly change D(V/K). ADH+ deermice exhibited D(V/K) values of 1.87 +/- 0.06 (untreated), 1.71 +/- 0.13 (pretreated with 3-amino-1,2,4-triazole), and 1.24 +/- 0.13 (after the ADH inhibitor, 4-methylpyrazole) at 5-7 mM blood ethanol levels. At elevated blood ethanol concentrations (58.1 +/- 2.4 mM), a D(V/K) of 1.37 +/- 0.21 was measured in the ADH+ strain. For measured D(V/K) values to accurately reflect pathway contributions, initial reaction conditions are essential. These were shown to exist by the following criteria: negligible fractional conversion of substrate to product and no measurable back reaction in deermice having a reversible enzyme (ADH). Thus, calculations from D(V/K) indicate that, even when ADH is present, non-ADH pathways (mostly MEOS) participate significantly in ethanol metabolism at all concentrations tested and play a major role at high levels.
Highlights
From the Alcohol Research and Treatment Center, Veterans Administration Medical Center, Bronx, New York 10468 and Mount Sinai School of Medicine, New York, New York I0029
Even in thAe DH' strain, MEOSmetabolizes a signifmicrosomal ethanol-oxidizing system (MEOS), and catalase) icantfraction of ethanol, especially a t high blood ethanol havebeen proposed tocontributetothe metabolism of concentrations
The ratio of 3H to "C in acetate divided by that in ethanol was In Vitro D(V/K) and Activity Measurements for ADH, Catahe, different from 1.0 in these experiments, it was divided intothe and MEOS-MEOS and catalase isotope effects were determined in uncorrected D( V/K) to obtain a final D( V/K) value
Summary
Vol 262, No 16, Issue of June 5, PP. 7497-7503,1987 Printed in U.S.A. From the Alcohol Research and Treatment Center, Veterans Administration Medical Center, Bronx, New York 10468 and Mount Sinai School of Medicine, New York, New York I0029. (one having and one lacking hepatic alcohol dehydro- raised the possibility of significant ethanol elimination by a genase (ADH))were used to calculate flux through the non-ADH pathwayi n vivo. ADH, microsomal ethanol-oxidizing system (MEOS), to be important aetlevated ethanol levels due to and catalase pathways. With the use of inhibitors in the ADH- strain and partially circumvents them in the ADH' strain Application of this technique t o deermice yielded results indicating that MEOS accounts formost in vivo ethanoloxidationinthe ADH-. Even in thAe DH' strain, MEOSmetabolizes a signifmicrosomal ethanol-oxidizing system (MEOS), and catalase) icantfraction of ethanol, especially a t high blood ethanol havebeen proposed tocontributetothe metabolism of concentrations.
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