The role of alcohol dehydrogenase in the hepatic necrosis due to allyl alcohol was studied in two strains of the deermouse, Peromyscus maniculatm. Mice of the alcohol dehydrogenase-negative (AdhN) strain which lack alcohol dehydrogenase activity were resistant to allyl alcohol toxicity. In contrast, dose-dependent necrosis of periportal regions of the liver and increases in plasma levels of lactate dehydrogenase, sorbitol dehydrogenase and SGOT were observed in plasma from alcohol dehydrogenase-positive deermice (A&? 24 hr following administration of allyl alcohol (21 to 84 mg per kg). Half-maximal damage to periportal areas was observed with about 52 mg per kg allyl alcohol. Thus, these data demonstrate that metabolism of allyl alcohol to acrolein by alcohol dehydrogenase is obligatory for the bepatotoxicity of allyl alcohol.
Allyl alcohol has long been known to cause necrosis in periportal regions of the liver lobule (1). It was proposed that this zonal hepatotoxicity resulted from the NAD+dependent oxidative metabolism of allyl alcohol to acrolein by liver alcohol dehydrogenase (ADH) exclusively in periportal regions of the liver lobule (2). This hypothesis was based on the fact that pretreatment of rats with 4methylpyrazole, an inhibitor of ADH, prevented this damage (2) and on one report which showed that ADH activity determined histochemically was slightly higher in periportal than in pericentral regions of the liver lobule (3). However, 4-methylpyrazole also inhibits mixed-function oxidation (4, 5) and most likely would inhibit the monooxygenation of allyl alcohol to glycidol by cytochrome P-450 (6-8). Furthermore, ADH activity determined microchemically was greater in pericentral areas (9), and rates of allyl alcohol metabolism determined in perfused rat liver using microlight guides to monitor changes in NADH fluorescence were actually slightly greater in pericentral than in periportal regions of the