Rates of allyl alcohol metabolism in periportal and pericentral regions of the liver lobule

SA Belinsky, T Matsumura, FC Kauffman and RG Thurman

Rates of allyl alcohol metabolism in periportal and pericentral regions of the liver lobule were measured to determine whether the zonal toxicity due to allyl alcohol results from its selective metabolism in periportal regions. Infusion of allyl alcohol into perfused livers from fed, phenobarbital-treated rats caused an increase in NADH fluorescence (366 leads to 450 nm) measured with a large-tipped (2-mm) light guide placed on the surface of the liver. A linear increase in NADH fluorescence was observed when 25-150 microM allyl alcohol was infused; however, when allyl alcohol exceeded 200 microM, oxygen uptake by the liver was inhibited 30-40%, and a large increase in NADH fluorescence occurred. Miniature oxygen electrodes were then placed on periportal and pericentral regions of the liver lobule and local rates of oxygen uptake were determined [Matsumura and Thurman, Am. J. Physiol. 244:G656- G659 (1983)]. Allyl alcohol (350 microM) or acrolein (200 microM) inhibited oxygen uptake only in periportal regions. Micro-light guides were placed on periportal and pericentral regions of livers perfused in either the anterograde or retrograde direction. The maximal increase in NADH fluorescence due to allyl alcohol infusion (100 microM) was greater in pericentral than in periportal regions. 4-Methylpyrazole (80 microM), an inhibitor of alcohol dehydrogenase, prevented the fluorescence increase due to allyl alcohol in both regions, indicating that the changes were due entirely to NADH generated from alcohol dehydrogenase-dependent allyl alcohol metabolism. Using the correlation (r = 0.91) between rates of allyl alcohol uptake and the increase in NADH fluorescence established for the whole organ, local rates of allyl alcohol metabolism were 23 and 31 mumoles/g/hr in periportal and pericentral regions, respectively. These results indicate that metabolism of allyl alcohol occurs at slightly greater rates in pericentral than in periportal regions of the liver lobule. Thirty minutes after the i.p. injection of a necrogenic dose of allyl alcohol in vivo, the concentrations of allyl alcohol in the portal vein and vena cava were 1210 and 530 microM, respectively. Thus, both periportal and pericentral regions of the liver lobule were exposed to concentrations of allyl alcohol (e.g., greater than 200 microM) which were metabolized in the perfused liver. Since allyl alcohol is metabolized in both regions of the liver lobule, the hypothesis that the zone-specific hepatotoxicity results from its exclusive metabolism to acrolein in periportal regions seems unlikely.

Volume 25, Issue 1, pp. 158-164, 01/01/1984
Copyright © 1984 by American Society for Pharmacology and Experimental Therapeutics