Chloroacetaldehyde-induced hepatocyte cytotoxicity. Mechanisms for cytoprotection.

Abstract:

:2-Chloroacetaldehyde (CAA)-induced cytotoxicity in isolated hepatocytes was enhanced markedly if hepatocyte alcohol or aldehyde dehydrogenase was inhibited prior to CAA addition. Hepatocyte GSH depletion, ATP depletion and lipid peroxidation by CAA were also enhanced markedly. Furthermore, CAA was about 10- and 70-fold more cytotoxic than its oxidative or reductive metabolite chloroacetate or chloroethanol, respectively. Nutrients such as lactate, xylitol, sorbitol or glycerol, which increase cytosolic NADH levels, prevented CAA cytotoxicity in normal hepatocytes but further enhanced cytotoxicity toward alcohol dehydrogenase inactivated hepatocytes, suggesting that increased cytosolic NADH reduces CAA via alcohol dehydrogenase in normal hepatocytes but prevents CAA oxidation in alcohol dehydrogenase inactivated hepatocytes. However, increasing cytosolic NADH levels with ethanol or NADH-generating nutrients after CAA had been metabolized also prevented cytotoxicity and caused a partial ATP recovery, whereas oxidation of cytosolic NADH with pyruvate markedly increased cytotoxicity. This indicates that cytotoxic CAA concentrations cause oxidative stress and that ATP levels can be restored if cellular redox homeostasis is normalized with reductants. Furthermore, except for fructose, nutrients that did not increase NADH did not affect CAA-induced cytotoxicity. Fructose also caused a partial ATP recovery, and its protection was prevented by the glycolytic inhibitor fluoride. Hepatocytes isolated from fasted animals were 4- to 6-fold more susceptible to CAA-induced ATP depletion and cytotoxicity. No lipid peroxidation occurred at these lower CAA concentrations. Furthermore, all nutrients, including alanine, glutamine and glucose, prevented cytotoxicity toward hepatocytes isolated from fasted animals. The susceptibility of hepatocytes to CAA cytotoxicity, therefore, depends on both cellular redox homeostasis and cellular energy supply.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Sood C,O'Brien PJ

doi

10.1016/0006-2952(94)90374-3

subject

Has Abstract

pub_date

1994-08-30 00:00:00

pages

1025-32

issue

5

eissn

0006-2952

issn

1873-2968

pii

0006-2952(94)90374-3

journal_volume

48

pub_type

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