Interindividual Differences in Nicotine Metabolism and Genetic Polymorphisms of Human Cyp2a6

Nakajima, Miki; Kuroiwa, Yukio; Yokoi, Tsuyoshi

doi:10.1081/dmr-120015696

Cited by 64 publications

(40 citation statements)

References 43 publications

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“…The CYP2A6*5 (¿0.5z), CYP2A6*6 (¿0.4z), CYP2A6 * 10 (0.5-1.1z), and CYP2A6 * 11 (¿0.7z) alleles were rare, and the CYP2A6*2 allele was not found. 30,31) We found that cotinine formation was impaired in the homozygotes of either CYP2A6*4, CYP2A6*7 and CYP2A6*10 ( Fig. 2).…”

Section: Interindividual Dišerences In Cotinine Formation Andmentioning

confidence: 91%

Interindividual Variability in Nicotine Metabolism: C-Oxidation and Glucuronidation

Nakajima

Yokoi

2005

Drug Metabolism and Pharmacokinetics

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Summary: Nicotine has roles in the addiction to smoking, replacement therapy for smoking cessation, as a potential medication for several diseases such as Parkinson's disease, Alzheimer's disease, and ulcerative colitis. The absorbed nicotine is rapidly and extensively metabolized and eliminated to urine. A major pathway of nicotine metabolism is C-oxidation to cotinine, which is catalyzed by CYP2A6 in human livers. Cotinine is subsequently metabolized to trans-3?-hydroxycotinine by CYP2A6. Nicotine and cotinine are glucuronidated to N-glucuronides mainly by UGT1A4 and partly by UGT1A9. Trans-3?-hydroxycotinine is glucuronidated to O-glucuronide mainly by UGT2B7 and partly by UGT1A9. Approximately 90z of the total nicotine uptake is eliminated as these metabolites and nicotine itself. The nicotine metabolism is an important determinant of the clearance of nicotine. Recently, advances in the understanding of the interindividual variability in nicotine metabolism have been made. There are substantial data suggesting that the large interindividual diŠerences in cotinine formation are associated with genetic polymorphisms of the CYP2A6 gene. Interethnic diŠerences have also been observed in the cotinine formation and the allele frequencies of the CYP2A6 alleles. Since the genetic polymorphisms of the CYP2A6 gene have a major impact on nicotine clearance, its relationships with smoking behavior or the risk of lung cancer have been suggested. The metabolic pathways of the glucuronidation of nicotine, cotinine, and trans-3?-hydroxycotinine in humans would be one of the causal factors for the interindividual diŠerences in nicotine metabolism. This review mainly summarizes recent results from our studies.

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Section: Interindividual Dišerences In Cotinine Formation Andmentioning

confidence: 91%

Interindividual Variability in Nicotine Metabolism: C-Oxidation and Glucuronidation

Nakajima

Yokoi

2005

Drug Metabolism and Pharmacokinetics

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confidence: 99%

“…The systemic clearance was increased by 60% and 140% for nicotine and cotinine, respectively, in pregnancy compared with postpartum. This increase is most likely mediated by the induction of cytochrome P450 2A6, the main enzyme metabolizing nicotine and cotinine [8].Urine samples were collected and nicotine and metabolite concentrations were analysed by gas chromatography -mass spectrometry [7]. We have now reanalysed the data to examine the effects of pregnancy on the urinary ratio of nicotine N ¢ -oxide/nicotine, as an index of FMO3 activity.…”

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confidence: 99%

Effect of pregnancy on a measure of FMO3 activity

Hukkanen¹,

Dempsey²,

Jacob³

et al. 2005

Brit J Clinical Pharma

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Flavin-containing monooxygenases (FMO) are a family of microsomal enzymes that catalyse the oxygenation of xenobiotics [1]. Six FMO genes exist in humans, but only FMO3 enzyme is abundantly expressed in human liver. FMO3 contributes to the metabolism of several drugs including methimazole, nicotine, cimetidine, ranitidine, tamoxifen, and clozapine [1,2]. Dysfunctional FMO3 enzymes with deficient N-oxygenation of dietary trimethylamine cause trimethylaminuria (fish-odour syndrome).FMO3 is the main enzyme responsible for nicotine N ¢ -oxide formation, which is a minor pathway of nicotine metabolism. The FMO content of human liver microsomes is correlated with nicotine N ¢ -oxide formation, and N ¢ -oxygenase activity is abolished by FMO inhibitors in vitro [3]. Also, cDNA-expressed FMO3 is active in nicotine N ¢ -oxide formation [4]. A preliminary report on two siblings with fish-odour syndrome showed impaired urinary excretion of nicotine N ¢ -oxide compared with normal subjects [5]. Methimazole, an antithyroid agent and FMO3 inhibitor, has been reported to reduce nicotine N ¢ -oxide excretion [6]. Thus, formation of nicotine N ¢ -oxide can be used as a probe of human FMO3 activity [1].We recently published a study on pregnant smokers investigating the effect of pregnancy on nicotine and cotinine metabolism [7]. Ten subjects were given deuterium-labelled nicotine-d 2 and cotinine-d 4 infusion (30 or 45 m g/kg -1 of each compound) during pregnancy and postpartum. The systemic clearance was increased by 60% and 140% for nicotine and cotinine, respectively, in pregnancy compared with postpartum. This increase is most likely mediated by the induction of cytochrome P450 2A6, the main enzyme metabolizing nicotine and cotinine [8].Urine samples were collected and nicotine and metabolite concentrations were analysed by gas chromatography -mass spectrometry [7]. We have now reanalysed the data to examine the effects of pregnancy on the urinary ratio of nicotine N ¢ -oxide/nicotine, as an index of FMO3 activity. Ten subjects completed the study; a urine sample from one subject was lost. We measured both nicotine N ¢ -oxide-d 2 and nicotine-d 2 concentrations in urine samples collected over 8 h following the infusion in nine subjects during pregnancy and postpartum. In two subjects the calculation of the urine ratio during pregnancy was not possible because the concentration of nicotine (one subject) or concentration of nicotine N ¢ -oxide (one subject) was below the limit of quantification. In the remaining subjects the ratio of nicotine N ¢ -oxide/nicotine was substantially increased during pregnancy compared with postpartum (2.03 vs. 0.78; paired t-test, P = 0.017; 95% CI of the difference 0.5-2.0) ( Table 1).A possible confounding factor is that renal clearance of nicotine is pH-dependent, whereas nicotine N ¢ -oxide excretion is not. On average, pregnancy increases urine pH by 0.3-0.4 units [9] and might increase the nicotine N ¢ -oxide/nicotine ratio by decreasing nicotine excretion. Urine pH values were not recorded...

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“…One of the polymorphisms involving CYP2A6 is related to the genetic variation across different ethnic populations. The percentage of slow metabolizers in the Asian population is larger (10-20%) when compared to Caucasians (1.2%) (39). In addition, the CYP2A6 activity in women is greater than in men.…”

Section: Drug Interactionsmentioning

confidence: 79%

The use of aromatase inhibitors in boys with short stature: what to know before prescribing?

Linardi¹,

Damiani

Longui

2017

Arch. Endocrinol. Metab.

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Aromatase is a cytochrome P450 enzyme (CYP19A1 isoform) able to catalyze the conversion of androgens to estrogens. The aromatase gene mutations highlighted the action of estrogen as one of the main regulators of bone maturation and closure of bone plate. The use of aromatase inhibitors (AI) in boys with short stature has showed its capability to improve the predicted final height. Anastrozole (ANZ) and letrozole (LTZ) are nonsteroidal inhibitors able to bind reversibly to the heme group of cytochrome P450. In this review, we describe the pharmacokinetic profile of both drugs, discussing possible drug interactions between ANZ and LTZ with other drugs. AIs are triazolic compounds that can induce or suppress cytochrome P450 enzymes, interfering with metabolism of other compounds. Hydroxilation, N-dealkylation and glucoronidation are involved in the metabolism of AIs. Drug interactions can occur with azole antifungals, such as ketoconazole, by inhibiting CYP3A4 and by reducing the clearance of AIs. Antiepileptic drugs (lamotrigine, phenobarbital, and phenytoin) also inhibit aromatase. Concomitant use of phenobarbital or valproate has a synergistic effect on aromatase inhibition. Therefore, it is important to understand the pharmacokinetics of AIs, recognizing and avoiding possible drug interactions and offering a safer prescription profile of this class of aromatase inhibitors. Arch Endocrinol Metab. 2017;61(3):391-7.

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Interindividual Differences in Nicotine Metabolism and Genetic Polymorphisms of Human Cyp2a6

Cited by 64 publications

References 43 publications

Interindividual Variability in Nicotine Metabolism: C-Oxidation and Glucuronidation

Interindividual Variability in Nicotine Metabolism: C-Oxidation and Glucuronidation

Effect of pregnancy on a measure of FMO3 activity

The use of aromatase inhibitors in boys with short stature: what to know before prescribing?

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