RT Journal Article
SR Electronic
T1 METABOLISM OF NICOTINE AND COTININE BY HUMAN CYTOCHROME P450 2A13
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 258
OP 261
DO 10.1124/dmd.104.002105
VO 33
IS 2
A1 Ziping Bao
A1 Xiao-Yang He
A1 Xinxin Ding
A1 Saileta Prabhu
A1 Jun-Yan Hong
YR 2005
UL http://dmd.aspetjournals.org/content/33/2/258.abstract
AB 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 Km and Vmax values of 20.2 μM and 8.7 pmol/min/pmol, respectively. CYP2A13 also catalyzes the 3′-hydroxylation of cotinine to form trans-3′-hydroxycotinine, with the apparent Km and Vmax values of 45.2 μM and 0.7 pmol/min/pmol, respectively. The importance of CYP2A13-catalyzed nicotine and cotinine metabolism in vivo remains to be determined. The American Society for Pharmacology and Experimental Therapeutics