Cytochrome P450 2E1 metabolically activates propargyl alcohol: propiolaldehyde-induced hepatocyte cytotoxicity

Pargyline, an antihypertensive agent and monoamine oxidase inhibitor, induc es hepatic GSH depletion and hepatotoxicity in vivo in rats [E.G. De Master , H.W. Sumner, E. Kaplan, F. N. Shirota, H.T. Nagasawa, Toxicol. Appl. Phar macol. 65 (1982) 390-401]. Propargyl alcohol (2-propyn-1-ol), because of it s structural similarity to allyl alcohol, was thought to be activated by al cohol dehydrogenase. However, it is a poor substrate compared to allyl alco hol and it was therefore proposed that propargyl alcohol-induced liver inju ry involved metabolic activation by catalase/H2O2 [E.G. De Master, T. Dahls eid, B. Redfern, Chem. Res. Toxicol. 7 (1994) 414-419]. In the following we showed that; (1) propargyl alcohol-induced cytotoxicity was markedly enhan ced in CYP 2E1-induced hepatocytes and prevented by Various CYP 2E1 inhibit ors but was only slightly affected when alcohol dehydrogenase was inhibited with methylpyrazole/DMSO or when catalase was inactivated with azide or am inotriazole, (2) hepatocyte GSH depletion preceded cytotoxicity and was inh ibited by cytochrome P450 inhibitors but not by catalase/alcohol dehydrogen ase inhibitors. GSH conjugate formation during propargyl alcohol metabolism by microsomal mixed function oxidase in the presence of GSH was also preve nted by anti-rat CYP 2E1 or CYP 2E1 inhibitors, (3) cytotoxicity was preven ted when lipid peroxidation was inhibited with antioxidants, desferoxamine (ferric chelator) or dithiothreitol. Propargyl alcohol-induced cytotoxicity and reactive oxygen species formation were markedly increased in GSH-deple ted hepatocytes. All of this evidence suggests that propargyl alcohol-induc ed cytotoxicity involves metabolic activation by CYP 2E1 to form propiolald ehyde that causes hepatocyte lysis as a result of GSH depletion and lipid p eroxidation. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.