Metabolism of nicotine and cotinine by human cytochrome P450 2A13.
Nicotine, a major constituent of tobacco, plays a critical role in smoking addiction. In humans, nicotine is primarily metabolized to cotinine, which is further metabolized to trans-3'-hydroxycotinine. Recently, we have demonstrated that heterologously expressed human CYP2A13 is highly active in the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a nicotine-derived carcinogen. In the present study, CYP2A13-catalyzed NNK metabolism was found to be inhibited competitively by nicotine and N'-nitrosonornicotine (NNN), suggesting that both nicotine and NNN are also substrates of CYP2A13. We have further demonstrated that human CYP2A13 is indeed an efficient enzyme in catalyzing C-oxidation of nicotine to form cotinine, with the apparent K(m) and V(max) values of 20.2 microM and 8.7 pmol/min/pmol, respectively. CYP2A13 also catalyzes the 3'-hydroxylation of cotinine to form trans-3'-hydroxycotinine, with the apparent K(m) and V(max) values of 45.2 microM and 0.7 pmol/min/pmol, respectively. The importance of CYP2A13-catalyzed nicotine and cotinine metabolism in vivo remains to be determined.
Bao
Ziping
Z
School of Public Health, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA.
He
Xiao-Yang
XY
Ding
Xinxin
X
Prabhu
Saileta
S
Hong
Jun-Yan
JY
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D002273:Carcinogens / Q000378:metabolism; D003367:Cotinine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007313:Insecta; D008861:Microsomes / Q000378:metabolism; D009538:Nicotine / Q000378:metabolism*; D009602:Nitrosamines / Q000378:metabolism; D013379:Substrate Specificity
D002273:Carcinogens; D009602:Nitrosamines; D009538:Nicotine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D001189:Aryl Hydrocarbon Hydroxylases; C414206:CYP2A13 protein, human; D003367:Cotinine