Possible role of glutathione depletion in the induction of rate-limiting enzymes involved in heme degradation and polyamine biosynthesis in the liver of rats.

Ten compounds with a wide variety of structures, which decreased hepatic glutachione (GSH) content at an early time period after their administration, simultaneously increased hepatic heme oxygenase, ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC) activities in rats. The compounds examined were four alpha, beta-unsaturated carbonyl compounds, two prototype substrates for GSH transferase(s), one epoxide, two isothiocyanates, and an indicator of hepatic function test. Time course studies with 1-chloro-2,4-dinitrobenzene (CDNB) and 1,2-dichloro-4-nitrobenzene (DCNB), which are prototype substrates for GSH transferases, showed that there was an inverse relationship between the early depletion of hepatic GSH content and induction of heme oxygenase, ODC and SAMDC together with a decrease in cytochrome P-450 content and an increase in putrescine content. Buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, also increased heme oxygenase and SAMDC activities, but not ODC, and it tended to enhance the induction of the enzymes evoked by diethyl maleate (DEM), phorone and CDNB with the sustained depletion of GSH content. In contrast, GSH treatment inhibited DEM-, phorone-, and CDNB-mediated induction of these enzymes and the early depletion of GSH content. N-Acetylcysteine failed to inhibit DEM- and phorone-mediated induction of these enzymes and the early depletion of GSH content, while it inhibited somewhat these changes produced by CDNB. The findings suggest that the early depletion of hepatic GSH content is prerequisite for and plays a role in the induction of heme oxygenase, ODC and SAMDC.