Pharmaceutical study on the risk of endocrine disrupting chemicals based on the regulation of ketone body metabolism

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Acetoacetyl-CoA synthetase (AACS, acetoacetate-CoA ligase, EC 6.2.1.16) is a ketone body-utilizing enzyme, the physiological role of which remains unclear yet. In order to investigate the tissue distribution of AACS in human, cDNA encoding AACS was isolated from HepG2 cells. Amino acid sequence of human AACS deduced from the open reading frame showed high homology (89.3 %) with that of rat AACS and much less homology (43.7 %) with that of bacterial AACS. The expression level of the AACS mRNA was high in kidney, heart and brain, but low in liver, and the expression profile of AACS in the human brain was quite similar to that of 3-hydroxy-3-methylgmtaryl-CoA reductase. Next, in order to investigate the physiological role of AACS, effects of streptozotocin (STZ)-induced diabetes on the enzyme activity was investigated in rats. At 72 hr of the STZ administration, hepatic enzyme specific activity decreased to 23 % of its initial activity. However, the enzyme activities in non-hepatic tissues were not significantly affected by the STZ treatment. Feeding of rats with both 4% cholestyramine and 0.4 % pravastatin for 3 days remarkably increased the hepatic AACS activity and decreased the plasma ketone bodies level in the diabetic rats. These results suggest that AACS has important roles in the regulation of ketone body utilization in rat liver and that these hypocholesterolemic agents have the ability to remedy the impaired utilization of ketone bodies under the diabetic condition. Then, effects of administration of estradiol and bisphenol A on the AACS activity was investigated. AACS activity in the rat or MCF-7 cells was decreased by both substances. However, AACS activity in MCF-7/Adr^R cells, which does not express estrogen receptor, was not affected by bisphenol A, suggesting that bisphenol A action on the AACS expression is mediated by estrogen receptor.