An in vivo/in vitro study of allyl alcohol toxicity using enzyme inhibitors

By Pulci, R. - Moneta, D. - Dostert, P. - Brughera, M. - Scampini, G. - Castellino, S. - Carminati, P. - Mazue, G.

The aim of this study was to verify an in vitro model of hepatotoxicity, designed to assess the production of reactive species from biologically-inert chemicals through their metabolic transformation. One example is allyl alcohol, which produces acrolein through the action of the enzyme alcohol dehydrogenase. Acrolein is a highly hepatotoxic aldehyde which is detoxified to acrylic acid by aldehyde dehydrogenase (ALDH). A deficiency of this enzyme, common in some Asian populations, can give rise to pathological conditions of hepatotoxicity. Isolated rat hepatocytes were incubated with allyl alcohol with and without cyanamide, a known inhibitor of ALDH. The toxicity of allyl alcohol, assessed on the basis of release of glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT) and lactate dehydrogenase (LDH) into the culture medium, was dramatically increased by the addition of cyanamide. In vivo, the same treatment scheme was used in rats treated with allyl alcohol with or without cyanamide pretreatment. It was also demonstrated that allyl alcohol toxicity is dramatically enhanced by the addition of an aldehyde dehydrogenase inhibitor, as shown by plasma levels of hepatic enzymes (GOT, GPT and LDH) and by histological findings. We believe that this in vitro model, involving the use of enzyme inhibitors, could be useful for verification of the hypothesis that hepatotoxins, such as acrolein, are produced from some pharmaceutical and other chemical compounds.