The metabolite ratio as a function of chloral hydrate dose and intracellular redox state in the perfused rat liver.
Chloral hydrate (CH), an intermediate metabolite of trichloroethylene, is reduced to trichloroethanol (TCE) by alcohol dehydrogenase and aldehyde reductase, and is also oxidized to trichloroacetic acid (TCA) by the nicotinamide adenine dinucleotide (NAD)-dependent enzyme, CH dehydrogenase. Alcohol dehydrogenase requires reduced NAD (NADH), aldehyde reductase requires reduced nicotinamide adenine dinucleotide phosphate (NADPH) and CH dehydrogenase requires NAD to complete the reaction. It is unclear which reaction is predominant at the physiological redox level in intact liver cells. To study this question, we perfused the livers of well-fed rats with Krebs-Ringer buffer solution containing 0.1 mM pyruvate/1.0 mM lactate. The levels of TCE and TCA in the effluent were measured by gas chromatography, and the fluorescence of reduced pyridine nucleotides was measured with a surface fluorometer. When a low concentration (below 0.25 mM) of CH was administered, more TCA than TCE was produced. When a high concentration of CH was administered (over 0.5 mM), TCE production was greater. Reduced pyridine nucleotides decreased inversely with the CH concentration. Even at low CH concentrations, pyridine nucleotides were not reduced. When 10 mM lactate was added to the perfusate in order to reduce the pyridine nucleotides in the liver cells, the TCE/TCA ratio increased. On the other hand, the TCE/TCA ratio tended to fall following the addition of 5.0 mM pyruvate. In conclusion, the TCE/TCA ratio was altered according to the concentration of CH, and to the redox level of pyridine nucleotides in the liver.
D000818:Animals; D001711:Biotransformation; D002697:Chloral Hydrate / Q000008:administration & dosage / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006454:Hemoglobins / Q000378:metabolism; D066298:In Vitro Techniques; D007773:Lactates / Q000494:pharmacology; D019344:Lactic Acid; D008099:Liver / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D010477:Perfusion; D011725:Pyridines / Q000378:metabolism; D011773:Pyruvates / Q000494:pharmacology; D019289:Pyruvic Acid; D051381:Rats; D011919:Rats, Inbred Strains; D013050:Spectrometry, Fluorescence
D006454:Hemoglobins; D007773:Lactates; D011725:Pyridines; D011773:Pyruvates; D019344:Lactic Acid; D002697:Chloral Hydrate; D019289:Pyruvic Acid