The Metabolite Ratio as a Function of Chloral Hydrate Dose and Intracellular Redox State in the Perfused Rat Liver

Abstract

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.

Kinetics of chloral hydrate and its metabolites in male human volunteers

“…In contrast, following the third dose in the repeated dose experiment, there was essentially no effect on the C max of T-TCE. This interpretation is consistent with the formation of TCA from CH observed in perfused rat livers (Kawamato et al, 1987). It is also supported by the relative insensitivity of the proportion of formation of TCE and TCA from CH in cryopreserved in human hepatocytes.…”

Brain Tissue Oxygen: In Vivo Monitoring with Carbon Paste Electrodes

“…It causes general CNS depression by rapidly metabolizing into trichloroethanol and trichloroacetic acid [43]. Trichloroethanol is suspected to be the active substance for inducing anaesthesia [44] because, similar to barbiturates, it has the ability to prolong chloride influx induced by exogenous GABA [45].…”

Mode of action of liver tumor induction by trichloroethylene and its metabolites, trichloroacetate and dichloroacetate.

“…In most species, TCOH is rapidly glucuronidated and the glucuronide is secreted into the bile. It is then secreted into the small intestine, hydrolyzed back to TCOH in the gut, reabsorbed and available to either be oxidized to TCA through CH as an intermediate, or reconjugated with glucuronic acid (80)(81)(82)(83). Normal humans are proficient at glucuronidating TCOH relative to rodents, particularly mice (9,82).…”