Nicotine Metabolic Capability Following Cigarette Smoking in Japanese Smokers with CYP2A64/9 Genotype

Objectives: To investigate whether smoking induced-nicotine metabolism is reduced in Japanese intermediate metabolizers (IMs) possessing the cytochrome P450 (CYP) 2A6*4/*9 genotype, we compared urinary excretion of nicotine and its metabolites (cotinine and trans-3'-hydroxycotinine [3OH-cotinin...

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Veröffentlicht in:Jikeikai Medical Journal 2007, Vol.54 (1), p.11-19
Hauptverfasser: Setsuko AKIZUKI, Akihiro OHNISHI
Format: Artikel
Sprache:jpn
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Zusammenfassung:Objectives: To investigate whether smoking induced-nicotine metabolism is reduced in Japanese intermediate metabolizers (IMs) possessing the cytochrome P450 (CYP) 2A6*4/*9 genotype, we compared urinary excretion of nicotine and its metabolites (cotinine and trans-3'-hydroxycotinine [3OH-cotinine] catalyzed by CYP2A6) between IMs and extensive metabolizers (EMs). We also compared the saliva levels of nicotine and cotinine with blood levels after cigarette smoking and analyzed the kinetic disposition. Study design : The subjects were 10 male smokers : 3 IMs (CYP2A6*4/*9) and 7 EMs (1 with CYP2A6*1/*4, 2 with *1/*9, and 4 with *1/*1). After abstaining from smoking for 3 days, the subjects smoked 3 cigarettes, and then serial blood and saliva samples were collected at given time intervals and timed urine specimens were collected. Percent urinary excretion of nicotine and its metabolites and the metabolic ratio or index as an indication of in vivo CYP2A6 activity were compared between IMs and EMs. Results : The 24-hour urinary excretion of nicotine as a percentage of total nicotine intake was significantly higher in IMs (37.0±6.9) than in EMs (16.3±2.4%, p<0.05). Conversely, urinary excretion of cotinine + 3OH-cotinine as a percentage of total nicotine intake was slightly but not significantly lower in IMs (63.0±6.9) than in EMs (83.8±2.4%, p=0.30). Metabolic clearance (239.8±98.4 vs. 959.9±264.4 ml/min, p<0.05) and metabolic index (10.4±21.3 vs. 39.3±11.7 mL/min, p<0.05) were also lower in IMs than in EMs. Nicotine and cotinine levels in saliva were much higher than in serum (nicotine : 21 to 37 times higher during the first 3 hours ; cotinine : 1.9 to 3.4 times higher up to 24 hours). Conclusion : These results suggest that nicotine metabolism via CYP2A6 is moderately suppressed in Japanese subjects with the CYP2A6*4/*9 genotype compared with that in EMs. Nicotine and cotinine appear to be secreted to a great extent in saliva, and the salivary level may be an excellent substitute for the serum level.
ISSN:0021-6968