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 alcohols (16 saturated and 7 unsaturated) in the isolated perfused rat liver at a concentration of 65.1 mmol/l (approximately 0.3% ethanol). The capacity of the straight chain primary alcohols (methanol, ethanol, 1-propanol, 1-butanol and 1-pentanol) to release the enzymes glutamate-pyruvate transaminase (GPT), lactate dehydrogenase (LDH) and glutamate dehydrogenase (GLDH) into 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 accompanied by an increase in toxicity. An increased enzyme release was in general accompanied by, and correlated to, reductions in oxygen consumption, bile secretion, and perfusion flow of the isolated livers. Statistically significant correlations exist between parameters of alcohol-induced hepatotoxicity and the membrane/buffer partition coefficents of the alcohols. With the exception of methanol, all alcohols tested increased the lactate/pyruvate ratio of the perfusate, although this effect was not correlated to the degree of hepatic injury. Hepatic ATP concentrations decreased in most cases in line with hepatic injury and were particularly correlated with changes in oxygen consumption. Hepatic concentrations of reduced glutathione (GSH) were only diminished by the unsaturated alcohols, whereas an increase in hepatic oxidized glutathione (GSSG) occurred only with some of the saturated alcohols. Hepatic concentrations of malondialdehyde (MDA) increased after two saturated and three unsaturated alcohols but did not correlate with other parameters of hepatotoxicity. In conclusion, alcohol-induced hepatotoxicity is primarily due to membrane damage induced by the direct solvent properties of the alcohols. The consequences and relative contributions of alcohol metabolization to the overall hepatotoxicity of higher alcohols requires further study.
Strubelt
O
O
Institut für Toxikologie der Medizinischen Universität zu Lübeck, Germany.
Deters
M
M
Pentz
R
R
Siegers
C P
CP
Younes
M
M
D015104:3,4-Methylenedioxyamphetamine / Q000032:analysis; D000255:Adenosine Triphosphate / Q000378:metabolism; D000410:Alanine Transaminase / Q000378:metabolism; D000438:Alcohols / Q000145:classification / Q000633:toxicity*; D000818:Animals; D001646:Bile / Q000378:metabolism; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D005978:Glutathione / Q000032:analysis; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000032:analysis; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D019289:Pyruvic Acid / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013329:Structure-Activity Relationship
D000438:Alcohols; D019344:Lactic Acid; D015104:3,4-Methylenedioxyamphetamine; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D005969:Glutamate Dehydrogenase; D000410:Alanine Transaminase; D005978:Glutathione