Cytochrome P450 2A6 is involved in the metabolism of nicotine and the activation of carcinogenic nitrosamines. It is expressed in the liver and several extrahepatic tissues including lung and nasal mucosa. Genetic variability of CYP2A6 is considerable and has clinical implications. CYP2A6 polymorphisms are suggested to influence smoking behavior and cancer risk (Pianezza et al., 1998 and Kamataki et al., 1999). The clearance of letrozole, an aromatase inhibitor, can be altered by CYP2A6 variants (Desta et al., 2010). While the relationship between CYP2A6 polymorphisms and nicotine metabolism is established, the impact of dietary constituents and other xenobiotics as CYP2A6 modulators is less understood. With this in mind, cinnamic aldehyde and related analogs were assessed for their capacity to modulate CYP2A6 activity in vitro. Cinnamic aldehyde is the major constituent in cinnamon oil and is present in a variety of foods, gums, cosmetic products, and supplements. Of three cinnamic derivatives cinnamic aldehyde displayed the greatest potency in IC50 studies (IC50 = 7.0 µM; IC50 = 354.4 µM and IC50 > 2500 µM for cinnamic alcohol and cinnamic acid, respectively). Cinnamic aldehyde also exhibited time and NADPH dependent inhibition of coumarin hydroxylase activity (KI = 21.0 µM and kinact = 0.038 min-1). Molecular modeling identified five amino acids interacting with cinnamic aldehyde and threonine 305 was identified as a potential site for covalent modification by a reactive metabolite generated from activation of cinnamic aldehyde. The investigation of this model Michael acceptor molecule will facilitate the understanding of the molecular mechanism of CYP2A6 inactivation by phenylpropanoids.
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