Comparative specificities of Calreticulin Transacetylase to O-acetyl, N-acetyl and S-acetyl derivative of 4-methylcoumarins and their inhibitory effect on AFB₁-induced genotoxicity in vitro and in vivo

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• 作者：Ajit Kumar^a ; ^{ajitvpci@gmail.com} ; Prija Ponnan^a ; ^b ; Hanumantharao G. Raj^a ; ¹ ; Virinder S. Parmar^b ; Luciano Saso^c
• 关键词：Aflatoxin B1 ; Cytochrome-P-450 ; Calreticulin Transacetylase ; 7-Acetamido-4-methylcoumarin ; 7-Thioacetyl-4-methylcoumarin
• 刊名：Food and Chemical Toxicology
• 出版年：2013
• 出版时间：February, 2013
• 年：2013
• 卷：52
• 期：Complete
• 页码：216-224
• 全文大小：670 K

文摘

We have earlier conclusively established the Calreticulin Transacetylase (CRTAase) catalyzed modifications of functional proteins such as cytochrome-P450-linked mixed function oxidases (Cyt-P450-linked MFOs), NADPH cytochrome c reductase, and glutathione S-transferase by acetoxy derivatives of polyphenols. In this study, we have investigated the comparative specificities of CRTAase to N-acetyl derivative, 7-acetamido-4-methylcoumarin (7-N-AMC), O-acetyl derivative, 7-acetoxy-4-methylcoumarin (7-AMC), S-acetyl derivative, 7-thioacetyl-4-methycoumarin (7-S-AMC) and their parent compounds in the modulation of catalytic activities of aforesaid proteins. Special attention concentrated on the comparative inhibitory effect of aforesaid acetyl moiety on Cyt-P450-linked MFOs such as 7-ethoxyresorufin O-deethylase (EROD), pentoxyresorufin O-dealkylase (PROD) and aflatoxin B₁ (AFB₁)-induced genotoxicity in vitro and in vivo. The results clearly indicated that N-acetyl and O-acetyl derivatives were better substrates for CRTAase while the S-acetyl was found to be a poorer substrate. Our study involving atomic charge, charge density and molecular electrostatic potential (MEP) calculations indicated the pivotal role of electronegativity and charge distribution values of O, N and S atoms of the acetyl group at C-7 position of the 4-methylcoumarins in CRTAase activity. These facts reinforce our hypothesis that the CRTAase catalyzed modifications of the catalytic activities of aforesaid proteins by acetyl derivative of 4-methylcoumarins is probably due to acetylation of these proteins.