The toxic and metabolic effects of 23 aliphatic alcohols in the isolated perfused rat liver

We investigated the acute toxic and metabolic effects of 23 aliphatic alcoh ols (16 saturated and 7 unsaturated) in the isolated perfused rat liver at a concentration of 65.1 mmol/l (approximate to 0.3% ethanol), The capacity of the straight chain primary alcohols (methanol, ethanol, l-propanol, l-bu tanol and l-pentanol) to release the enzymes glutamate-pyruvate transaminas e (GPT), lactate dehydrogenase (LDH) and glutamate dehydrogenase (GLDH) int o the perfusate was strongly correlated with their carbon chain length. The : secondary alcohols were less active in this respect whereas branching of the carbon chain did not consistently change alcohol toxicity. Unsaturation in the straight chain but not in the branched chain alcohols was accompani ed by an increase in toxicity. An increased enzyme release was in general a ccompanied by, and correlated to, reductions in oxygen consumption, bile se cretion, and perfusion flow of the isolated livers. Statistically significa nt correlations exist between parameters of alcohol-induced hepatotoxicity and the membrane/buffer partition coefficents of the alcohols. With the exc eption of methanol, all alcohols tested increased the lactate/pyruvate rati o of the perfusate, although this effect was not correlated to the degree o f hepatic injury. Hepatic ATP-concentrations decreased in most;cases in lin e with hepatic injury and were particularly correlated with changes in oxyg en consumption. Hepatic concentrations of reduced glutathione (GSH) were on ly diminished by the unsaturated alcohols, whereas an increase in hepatic o xidized glutathione (GSSG) occurred only with some of the saturated alcohol s. Hepatic concentrations of malondialdehyde (MDA) increased after two satu rated and three unsaturated alcohols but did not correlate with other param eters of hepatotoxicity. In conclusion, alcohol-induced hepatotoxicity is p rimarily due to membrane damage induced by the direct solvent properties of the alcohols. The consequences and relative contributions of alcohol metab olization to the overall hepatotoxicity of higher alcohols requires further study.