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.
Nishimaki-Mogami
T
T
National Institute of Hygienic Sciences, Tokyo, Japan.
Tanaka
A
A
Minegishi
K
K
Takahashi
A
A
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D000818:Animals; D002374:Catalase / Q000378:metabolism; D003065:Coenzyme A / Q000378:metabolism; D004032:Diet; D004746:Enoyl-CoA Hydratase / Q000096:biosynthesis* / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D044943:Fatty Acid Desaturases / Q000096:biosynthesis; D007535:Isomerases; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008830:Microbodies / Q000187:drug effects / Q000201:enzymology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D009097:Multienzyme Complexes / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D044925:Oxidoreductases Acting on CH-CH Group Donors; D063994:Peroxisomal Bifunctional Enzyme; D013011:Sorbic Acid / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*
D009097:Multienzyme Complexes; D015094:3-Hydroxyacyl CoA Dehydrogenases; D002374:Catalase; D044943:Fatty Acid Desaturases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C100153:2,4-dienoyl-CoA reductase; C070004:2,4-dienoyl-CoA hydratase; C576254:Ehhadh protein, mouse; D004746:Enoyl-CoA Hydratase; D063994:Peroxisomal Bifunctional Enzyme; D007535:Isomerases; D003065:Coenzyme A; D013011:Sorbic Acid