Toxicological and physiological significance of AADAC

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07082
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Kanazawa University
• Principal Investigator: Fukami Tatsuki 金沢大学, 薬学系, 准教授 (00532300)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 薬物代謝 / 脂質代謝 / 加水分解

Outline of Final Research Achievements

Arylacetamide deacetylase (AADAC) has been recognized as a drug-hydrolyzing enzyme. In this study, the preference of human AADAC for the hydrolysis of drugs containing acetyl group was clarified using eslicarbazepine acetate and abiraterone acetate. In addition, the acetylated metabolites of some N-acetyltransferase (NAT) substrates were hydrolyzed by AADAC. In fact, when nitrazepam was orally treated, the plasma concentration of N-acetylaminonitrazepam, which is produced by NAT, in Aadac knockout mice was higher than that in wild-type mice.
In addition to drug metabolism, AADAC is likely involved in the metabolism of endogenous compounds. When fatty acids were treated with cells, in where AADAC is overexpressed or knocked down, intracellular lipid accumulation was attenuated or increased, respectively. In treatment of high fat diet, Aadac knockout mice showed the higher plasma lipids including cholesterol than wild-type mice. Thus, AADAC would be involved in the lipid homeostasis.

Free Research Field

薬物代謝学、毒性学

Academic Significance and Societal Importance of the Research Achievements

臨床で使用されている医薬品の約10%は加水分解されることで薬効を失ったり、獲得したりするだけでなく、毒性を発揮する原因物質が生成される場合もある。医薬品の多くはカルボキシルエステラーぜにより加水分解されるとされてきたが、近年開発された医薬品ではアリルアセタミドデアセチラーゼ (AADAC)により加水分解されるものも散見される。AADACの基質認識性や薬物動態に与える影響の解明は医薬品の開発および適正使用にて重要な情報源となる。また、AADACが脂質代謝に関与することも初めて実験学的に明らかにした。現在、生活習慣病の罹患者が増えていることからも、AADACの機能解明は大きな意味を持つ。