Other Titles:
Inhibitory studies of the human cytochrome P450, CYP2A6, the nicotine metabolizing enzyme by Thai herbal and fruit juices
Abstract:
Cytochrome P450 2A6 (CYP2A6) is the heme-containing protein that belongs to the cytochrome P450 (CYP or P450) super-family. In human, P450 enzymes play an essential role in metabolism of various endogenous and exogenous compounds such as hormones drugs and many environmental toxicants. The human CYP2A6 enzyme could specifically metabolize nicotine, an additive compound in cigarette, with high efficiency (low Km and high Vmax value). Therefore, nicotine metabolism by the liver-specific human CYP2A6 enzymes has been report as an important route in nicotine detoxification. In addition, some of deficient CYP2A6 allele smokers that drastically decrease in nicotine metabolizing activity of CYP2A6 enzyme tend to smoke few cigarettes per day and are low-risk of nicotine dependence compared to the normal allele smokers. This study aims to screen for Thai herbal juices or fruit juices that could specifically inhibit CYP2A6 enzymatic activity in vitro. As the results, the bacterially expressed and purified human CYP2A6 enzyme is functionally active and is specifically metabolized the coumarin substrate with the Km value approximately 1 uM. Out of 25 herbal and fruit juices tested, an in vitro experiment indicated that only 3% v/v of the Star fruit juice could inhibit CYP2A6-mediated coumarin hydroxylation by 50%. Interestingly, almost 95% of CYP2A6-mediated coumarin hydroxylation was inhibited in the presense of 40% v/v of the Star fruit juice in vitro. Further study indicated Star fruit juice could inhibit CYP2A6 activity by mechanism-based inactivaition process. However, Star fruit juice could also inhibit human CYP3A4 and CYP2C9 activity in vitro. Therefore, care must be taken in cessation smokers who orally take drugs that metabolized by CYP3A4 and CYP2C9 enzyme, a highly distribute human-drug metabolizing enzymes.
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