Effect of sorbic acid feeding on peroxisomes and sorboyl-CoA metabolizing enzymes in mouse liver. Selective induction of 2,4-dienoyl-CoA hydratase.

On the basis of the finding that sorbic acid (SA)-induced hepatoma was correlated with the depletion of reduced glutathione (GSH) in mouse liver (Tsuchiya et al., Mutation Res 130: 267-262, 1984), the possible conversion of SA to a metabolite which is reactive with SH-compounds was studied. Sorboyl-CoA was hydrated and then reduced to 3-keto-4-hexenoyl-CoA by the combined actions of mitochondrial hydratase (crotonase) and L-3-hydroxyacyl-CoA dehydrogenase. Upon the addition of GSH or coenzyme A, 3-keto-4-hexenoyl-CoA was nonenzymatically converted to another 3-ketoacyl-CoA derivative, possibly a Michael type adduct, in a time- and concentration-dependent manner. Alternatively, sorboyl-CoA can be reduced by 2,4-dienoyl-CoA reductase and completely beta-oxidized without the generation of 3-keto-4-hexenoyl-CoA. Two-week feeding of mice of 15% SA caused a 2.0-fold induction of peroxisome beta-oxidation in the liver. SA caused a marked induction (3.6-fold) of hydratase toward sorboyl-CoA but a less pronounced induction (1.3-fold) of 2,4-dienoyl-CoA reductase, leading to about a 3-fold elevation in the hydratase: reductase ratio. The elevated ratio was sustained throughout the period of SA feeding up to 12 weeks. Thus, a large amount of SA could be converted to 3-keto-4-hexenoyl-CoA during this period. Oxidative stress caused by a depleted cellular SH-pool together with the induction of peroxisome proliferation by SA-feeding may implicate the mechanism by which non-mutagenic SA caused hepatoma.