Nicotine, metabolism

Kitts CL, LE Schaechter, RS Rabin, RA Ludwig (1989) Identification of cyclic intermediates in Azorhizobium caulinodans nicotinate metabolism. J Bacterial 171 3406-3411. 

Sachelaru P, E Schiltz, GL Igloi, R Brandsch (2005) An a/[5-fold C—C bond hydrolase is involved in a central step of nicotine metabolism by Arthrobacter nicotinovorans. J Bacteriol 187 8516-8519. 

Fig. 22.3 Cytochrome P450 monooxygenases and nicotine metabolism. An alignment of the amino acid sequences of the enzymes 2A6 and 2D6. Occurrences of the same amino acid residue at the same position are shown in black. Putative substrate recognition sites (SRS1—...

Effects of Genetically Determined Variation in Nicotine Metabolism on the Development of Nicotine Dependence... 

Smoking researchers may have to wait for more robust genetic assays before the issue is finally settled [30], but pharmacological inhibitors of CYP2A6 reduce smoking [31] and it seems likely that an inherited defect in nicotine metabolism would have the same effect. 

Accurate prediction of the rate of nicotine metabolism based on CYP2A6/D6 genotype could make adjusting the dose of nicotine replacement to avoid side effects and ensure effectiveness much simpler. It may be that information technology could help in making decisions about the choice [63] and dose [64] of drug based on genetic data. 

Nicotine metabolism defect reduces smoking. Nature 1998 393 750. 

Oscarson M et al. Identification and characterisation of novel polymorphisms in the CYP2A locus implications for nicotine metabolism. FEBS Lett 1999 ... 

Tyndale RF, Sellers EM. Genetic variation in CYP2A6-mediated nicotine metabolism alters smoking behavior. Ther Drug Monit 2002 24(1) 163-171. 

Fig. 3 Pathways of nicotine metabolism. Reprinted with permission from Hukkanen et at. 2005c...

Quantitative aspects of the pattern of nicotine metabolism have been elucidated fairly well in people (Fig. 4). Approximately 90% of a systemic dose of nicotine can be accounted for as nicotine and metabolites in urine (Benowitz et al. 1994). Based on studies with simultaneous infusion of labeled nicotine and cotinine, it has been determined that 70-80% of nicotine is converted to cotinine (Benowitz and Jacob 1994). About 4-7% of nicotine is excreted as nicotine N -oxide and 3-5% as nicotine glucuronide (Benowitz et al. 1994 Byrd et al. 1992). Cotinine is excreted unchanged in urine to a small degree (10-15% of the nicotine and metabolites in urine). The remainder is converted to metabolites, primarily fra i -3 -hydroxycotinine (33 0%), cotinine glucuronide (12-17%), and trans-3 -hydroxycotinine glucuronide (7-9%). 

Various enzymes involved in nicotine metabolism and their genetics are described in detail in the chapter by Mwenifumbo and Tyndale in this volume. 

An implication of the high degree of hepatic extraction is that clearance of nicotine should be dependent on liver blood flow. Thus, physiological events, such as meals, posture, exercise, or drugs perturbing hepatic blood flow, are predicted to affect the rate of nicotine metabolism. Meals consumed during a steady state infusion of nicotine result in a consistent decline in nicotine concentrations, the maximal effect seen 30-60 min after the end of a meal (Gries et al. 1996 Lee et al. 1989). Hepatic blood flow increases about 30% and nicotine clearance increases about 40% after a meal. 

Menthol is widely used as a flavorant in foods, mouthwash, toothpaste, and cigarettes. A moderate inhibition of CYP2A6-mediated nicotine metabolism in human... 

Clearance of nicotine is decreased in the elderly (age >65) compared to adults (Molander et al. 2001). Total clearance was lower by 23%, and renal clearance lower by 49% in the elderly compared to yonng adults. Lower nicotine metabolism in the elderly may be contribnted to by rednced liver blood flow, since no decrease in CYP2A6 protein levels or nicotine metabolism in liver microsomes due to age has been detected (Messina et al. 1997). No differences in steady-state nicotine plasma levels or estimated plasma clearance valnes were detected in three age gronps (18-39, 40-59, and 60-69 years) nsing patches with the same nicotine content (Gonrlay and Benowitz 1996). The volnme of distribntion of nicotine is lower in older snbjects due to a decrease in lean body mass (Molander et al. 2001). 

Neonates have diminished nicotine metabolism, as demonstrated by a nicotine half-life of three to four times longer in newborns exposed to tobacco smoke than in adnlts (Dempsey et al. 2000). Cotinine half-life is reported to be similar in neonates, older children, and adults in two studies (Dempsey et al. 2000 Leong et al. 1998). Other studies found that the half-life of urine cotinine was about three times longer in children less than one year old than to the cotinine half-life in adults (Collier et al. 1994). Urine cotinine half-life can be influenced by variations in urine volume and excretion of creatinine. The study by Dempsey et al. was the only one in which the half-life of cotinine was calculated based on both the blood and urine cotinine concentrations (Dempsey et al. 2000). In that study, both the blood and urine half-lives were similar to adult values, supporting the notion that neonates have the same cotinine half-life as older children and adults. 

Benowitz NL, Lessov-Schlaggar CN, Swan GE, Jacob P 3rd (2006) Female sex and oral contraceptive use accelerate nicotine metabolism. Clin Pharmacol Ther 79(5) 480 88 Benowitz N, Bernert JT, Caraballo RS, Holiday DB, Wang J (2008a) Optimal Serum Cotinine Levels to Distinguish Cigarette Smokers and Non-Smokers within Different Racial/Ethnic Groups in the United States Between 1999-2004. Am J Epidemiol (in press)... 

Dempsey D, Jacob P, 3rd, Benowitz NL (2000) Nicotine metabolism and elimination kinetics in newborns, din Pharmacol Ther 67(5) 458 65... 

Jacob P, 3rd, Benowitz NL (1991) Oxidative metabolism of nicotine in vivo. In F, Adlkofer, K, Thurau (eds) Effects of nicotine on biological systems, Birkhauser Verlag, Basel, pp 35 4 Jacob P, 3rd, Shulgin AT, Benowitz NL (1990) Synthesis of (3 R, 5 S)-trans-3 -hydroxycotinine, a major metabolite of nicotine. Metabolic formation of 3 -hydroxycotinine in humans is highly stereoselective, J Med Chem 33(7) 1888-1891... 

Johansson CJ, Olsson P, Bende M, Carlsson T, Gunnarsson PO (1991) Absolute bioavailabUity of nicotine applied to different nasal regions, Eur J Clin Pharmacol 41(6) 585-588 Johnstone E, Benowitz N, Cargill A, Jacob R, Hinks L, Day 1, Murphy M, Walton R (2006) Determinants of the rate of nicotine metabolism and effects on smoking behavior, Chn Pharmacol Ther 80(4) 319-330... 

Kyerematen GA, Morgan M, Warner G, Martin LF, VeseU ES (1990) Metabohsm of nicotine by hepatocytes, Biochem Pharmacol 40(8) 1747-1756 Le Gal A, Dreano Y, Lucas D, Berthou F (2003) Diversity of selective environmental substrates for human cytochrome P450 2A6 alkoxyethers, nicotine, coumarin, N-nitrosodiethylamine, and N-nitrosobenzylmethylamine, Toxicol Lett 144(1) 77-91 Lee BL, Benowitz NL, Jacob P 3rd (1987) Influence of tobacco abstinence on the disposition kinetics and effects of nicotine, Clin Pharmacol Ther41(4) 474 79 Lee BL, Jacob P 3rd, Jarvik ME, Benowitz NL (1989) Food and nicotine metabolism, Pharmacol Biochem Behav 33(3) 621-625... 

Schneider NG, Olmstead RE, Franzon MA, Lunell E (2001) The nicotine inhaler clinical pharmacokinetics and comparison with other nicotine treatments, Chn Pharmacokinet 40(9) 661-684 Schoedel KA, Sellers EM, Palmour R, Tyndale RF (2003) Down-regulation of hepatic nicotine metabolism and a CYP2A6-like enzyme in African green monkeys after long-term nicotine administration. Mol Pharmacol 63(1) 96-104... 

Stepanov I, Hecht SS, Lindgren B, Jacob P 3rd, Wilson M, Benowitz ML (2007) Relationship of human toenail nicotine, cotinine, and 4-(methylnitrosamino)-l-(3-pyridyl)-1-butanol to levels of these biomarkers in plasma and urine. Cancer Epidemiol Biomarkers Prev 16(7) 1382-1386 Swan GE, Benowitz NL, Lessov CN, Jacob P, 3rd, Tyndale RE, Wilhelmsen K (2005) Nicotine metabolism the impact of CYP2A6 on estimates of additive genetic influence. Pharmacogenet Genomics 15(2) 115-125... 

Zevin S, Jacob P 3rd, Benowitz N (1997) Cotinine effects on nicotine metabolism. Clin Pharmacol Ther61(6) 649-654... 

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