Heavily smoking women who cannot quit in pregnancy: evidence of pharmacokinetic predisposition

SUMMARY: Smoking in pregnancy is associated with a well-characterized increase in perinatal risks. Despite their wish to discontinue smoking, some pregnant women cannot stop. To characterize nicotine and cotinine levels in women who could not quit smoking after the first trimester, the authors recruited 19 white women (age 17-41 years) between 14-23 weeks of gestation who could not quit smoking. They started smoking at ages 11-22 years (mean 14.5) and smoked for 17 +/- 6 years. They had their first cigarettes 5-60 minutes after waking up (mean 12). Nicotine levels were compared with those expected in white patients in the general population, and the cotinine levels per cigarette smoked were compared with the population-based values. Sixteen of the 19 women had nicotine levels substantially lower than those expected. The mean level of serum cotinine produced by one cigarette per day was 19.1 +/- 15.8 ng/mL (range 6.1-67). The expected levels in white patients in the general population are 13 +/- 7.7 ng/mL. The data suggest that pregnant women who cannot quit heavy smoking in the second trimester form a selective group with pharmacokinetic predisposition to a high rate of nicotine metabolism.     

Effects of pregnancy on nicotine self-administration and nicotine pharmacokinetics in rats

Rationale Because of the adverse effects of smoking during pregnancy, understanding the factors that influence maternal smoking may help in developing better treatments to help women quit smoking during pregnancy. Animal models could be useful for this purpose. Objective The purpose of the present study was to begin the development of an animal model of smoking during pregnancy by initially characterizing nicotine self-administration (NSA) in pregnant rats. Another purpose was to begin to explore the effects of pregnancy on nicotine pharmacokinetics in rats. Materials and methods In experiment 1, female rats self-administering nicotine during 23-h sessions were examined throughout gestation and lactation. In experiment 2, locomotor activity was measured during pregnancy to assess further potential motor effects of pregnancy. Experiments 3 and 4 compared the single-dose pharmacokinetics of nicotine in male, nonpregnant female, and pregnant females in the first and third trimester of pregnancy and the first week of lactation. Results NSA decreased over the course of pregnancy with NSA significantly lower in the third trimester compared to nonpregnant controls. NSA remained suppressed for up to 10 days into lactation. Locomotor behavior was also significantly suppressed during the second and third trimesters and throughout lactation. Nicotine elimination was slower in pregnant females compared to nonpregnant females only in the third trimester. Conclusions NSA, locomotor behavior, and nicotine elimination in rats are decreased during late pregnancy. The present study is the first to characterize NSA during pregnancy in animals, providing a potential model of maternal smoking in humans.     

Reference values for hair cotinine as a biomarker of active and passive smoking in women of reproductive age, pregnant women, children, and neonates: systematic review and meta-analysis

Exposure to environmental tobacco smoke (ETS) is most often estimated using questionnaires, but they are unreliable. Biomarkers can provide valid information on ETS exposure, the preferred biomarker being cotinine. However, no reference range of hair cotinine exists to distinguish among active, passive, and unexposed nonsmokers. This study identifies cutoffs to validate cotinine as a marker for exposure to ETS. Data were obtained from six databases (four US, one Canada, one France). Active smoking and exposure to ETS were measured in the hair of women of reproductive age, pregnant women, their children, and neonates. Subjects were classified into active smokers, passively exposed to ETS, and unexposed nonsmokers. A total of 1746 cases were available for analysis. For active smokers, mean hair cotinine concentrations (95% confidence interval) were 2.3 to 3.1 ng/mg for nonpregnant women and 1.5 to 1.9 ng/mg for pregnant women. In the group of passive smokers, mean hair cotinine concentrations were 0.5 to 0.7 ng/mg for nonpregnant women, 0.04 to 0.09 ng/mg for pregnant women, 0.9 to 1.1 for children, and 1.2 to 1.7 for neonates. Among unexposed nonsmokers, mean hair cotinine was 0.2 to 0.4 ng/mg in nonpregnant women, 0.06 to 0.09 ng/mg in pregnant women, and 0.3 to 0.4 ng/mg in children. Cutoff values for hair cotinine were established to distinguish active smokers from passive or unexposed (0.8 ng/mg for nonpregnant women and 0.2 ng/mg for pregnant women). A cutoff value of 0.2 ng/mg was accurate in discriminating between exposed children and unexposed. These new values should facilitate clinical diagnosis of active and passive exposure to tobacco smoke. Such diagnosis is critical in pregnancy and in a large number of tobacco-induced medical conditions.     

Hair analysis--a biological marker for passive smoking in pregnancy and childhood.

Passive smoking has been shown to adversely affect the health of infants and children. We used hair analysis for nicotine and its metabolite cotinine as a biological marker for exposure to smoking in these two groups. Using radioimmunoassay we measured maternal and fetal hair concentrations of nicotine and cotinine in the mother-infant pairs belonging to three different groups based on the mother's smoking habits. The three groups were: active smokers, passive smokers and nonsmokers. There was a significant correlation between maternal and neonatal hair concentration for both, nicotine and cotinine. Mothers and infants in the smoking groups, both active and passive, had significantly higher hair concentrations of both, nicotine and cotinine than in the control, nonsmoking group. In an older cohort, we compared two groups: 78 asthmatic children were compared to 86 healthy children exposed to similar degrees of passive smoking. By using objective, biological markers, our study aimed at verifying whether asthmatic children are different from nonasthmatic children in the way their bodies handle nicotine. Our results show, that, despite the fact that parents of asthmatic children tend to smoke a lower number of cigarettes per day, their children had an average twofold higher concentrations of cotinine in their hair then the control, nonasthmatic children. These studies document the importance of hair analysis as a tool for measuring exposure to cigarette smoke.     

Correlation between self-reported smoking status and serum cotinine during pregnancy

Maternal smoking is associated with adverse perinatal outcomes. Because of concerns of underreporting, investigators routinely perform biochemical testing to confirm smoking status, such as serum cotinine, a major metabolite of nicotine, adding an increased cost to examine compliance. The objectives of this study were to determine the sensitivity and specificity of self-reported smoking with serum cotinine as the gold standard and to determine the correlation between self-reported smoking in cigarettes per day and serum cotinine levels. In this cross-sectional study, we surveyed women during the first trimester of pregnancy on their tobacco exposure. A total of 40 women reported that they were smokers, and 40 were nonsmokers, 1 of whom had quit 5 days prior. The mean (+/-S.D.) serum cotinine value among smokers was 155 (+/-122) ng/l, vs. 1 (+/-6) ng/l in nonsmokers, p<0.001. The sensitivity of self-reported smoking status was 97.6%, and the specificity was 100%. Comparing the reported number of cigarettes smoked and the serum cotinine level, the Spearman correlation coefficient was 0.92 (p=0.015) overall and 0.67 (p=0.088) for the subgroup of smokers. This study demonstrates that self-reported smoking exposure during pregnancy is highly accurate. The high correlation coefficient suggests that this is a robust surrogate for cotinine levels.     

孕晚期营养素摄入对新生儿出生体重的影响

目的探讨孕晚期营养素摄入状况对新生儿出生体重的影响。方法 1263例孕产妇及其新生儿,对其孕晚期营养摄入情况进行调查,分析孕晚期营养素摄入对新生儿出生体重的影响。结果 1263例孕妇年龄23~34岁,平均年龄(27.1±3.2)岁;孕周38~40周,平均孕周(39.3±0.5)周;分娩方式:阴道分娩1076例,剖宫产187例;共娩出1263例新生儿,均为活胎,男637例,女626例;体重2163~4118 g,平均体重(3233.8±357.0)g;未发生产科并发症及新生儿合并症;低出生体重(LBW)65例(5.15%)、正常体重(NW) 1105例(87.49%)、巨大儿(LBG) 93例(7.36%)。LBW新生儿、NW新生儿、LBG碳水化合物、脂肪、蛋白质、纤维、维生素C(VC)、铁、锌摄入量比较差异具有统计学意义(P<0.05);LBW新生儿、NW新生儿、LBG总热量、维生素A(VA)、维生素B1(VB1)、叶酸、钙摄入量比较差异无统计学意义(P>0.05)。Logistic回归分析显示:孕晚期碳水化合物、蛋白质、铁、锌摄入不足是LBW发生的危险因素,孕晚期碳水化合物、脂肪、锌摄入过多是LBG发生的危险因素。结论孕晚期碳水化合物、脂肪、蛋白质、铁、锌的摄入与新生儿体重密切相关,孕晚期应依据胎儿具体发育情况指导孕妇依据自身情况合理膳食,减少LBW及LBG的发生。     

TDM grand rounds: neonatal nicotine withdrawal syndrome in an infant prenatally and postnatally exposed to heavy cigarette smoke

A heavy smoking, lactating mother delivered a baby that exhibited spontaneous tremors, fluctuations of muscular rigidity, and opisthotonus at 48 hours of life. Although the symptoms did not disappear within the following days, they could be controlled by swaddling or wrapping the baby in a blanket. The absence of any other etiology generated a suspicion of prenatal exposure to heavy tobacco smoke and potential neonatal nicotine withdrawal syndrome. This diagnosis was supported by extremely high concentration of hair nicotine and cotinine in the infant's hair and in different segments of maternal hair. The presence of non-negligible amounts of nicotine and cotinine in breast milk confirmed that the mother did not quit smoking after delivery, despite her reports. The breast-fed newborn continued to have 3 to 4 crises of spontaneous tremors and alternant muscular rigidity per day for a month. More studies are needed to establish neonatal nicotine withdrawal.     

Interindividual variability in nicotine metabolism: C-oxidation and glucuronidation

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 90% 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 differences in cotinine formation are associated with genetic polymorphisms of the CYP2A6 gene. Interethnic differences 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 differences in nicotine metabolism. This review mainly summarizes recent results from our studies.     

Nicotine and metabolites in paired umbilical cord tissue and meconium specimens

Umbilical cord tissue was studied as a means of detecting prenatal exposure to nicotine. This was accomplished by comparing the presence and concentration of nicotine as well as nicotine metabolites in both umbilical cord tissue and paired meconium samples with maternal smoking histories obtained by self-report. Nicotine and metabolites (cotinine, 3-hydroxycotinine, nornicotine, and anabasine) were detected and quantitated using liquid chromatography-tandem mass spectroscopy. Between June and September 2009, 19 women with a tobacco exposure history (either first- or second-hand tobacco smoke exposure during pregnancy) were consented for the study. A questionnaire was completed to document nicotine exposure during each trimester of pregnancy. All infants were delivered at term (38 weeks or greater) and paired umbilical cord tissue (10-cm segment or greater) and meconium were obtained. Nicotine and 3-hydroxycotinine were most prominent in meconium, whereas cotinine and 3-hydroxycotinine were most prominent in the umbilical cord. Concentrations of all three analytes were generally higher in meconium. Nornicotine was detected only in meconium, at very low concentrations, and anabasine was not detected in either specimen. All analyte concentrations were lowest when the mother stated she quit smoking early in pregnancy or had only second-hand exposure, and detection was poor if exposure was limited to the first or second trimesters. Although different nicotine and metabolite patterns exist in meconium versus umbilical cord tissue, this work indicates that either specimen can be used to detect third-trimester fetal nicotine exposure.     

Changing patterns of soft drug use prior to and during pregnancy: A prospective study

Two hundred and seventeen women were interviewed during various stages of pregnancy to determine the extent and changing patterns of alcohol, nicotine and marihuana use in the year before pregnancy and during each trimester of pregnancy. Nutritional intake did not vary among women in the various drug using categories. Before pregnancy, 18% of the women were heavy social drinkers. During the first trimester this proportion was reduced by two-thirds and, in contrast to the other levels of social drinking, continued to decline during the last two trimesters. Age, income, education and smoking were all positively associated with heavy social drinking. Heavy cigarette smoking was reported by 13% of the women before pregnancy and by 8% during each of the trimesters. Education and income were negatively associated with heavy smoking. Three per cent of the women reported smoking more than five joints of marihuana per week before pregnancy and most continued to smoke marihuana heavily during pregnancy. The heavy marihuana users had a lower family income and less formal education than the overall sample. Marihuana use in general was associated with cigarette smoking and was not reported by women over 32 years of age. Except for heavy social drinking, soft drug habits at all levels of usage remained essentially unchanged after the first trimester. The likelihood of any one particular soft drug being reduced once pregnancy was established did not vary as a function of the concomitant use of other soft drug(s).     

A comparison of the effects of prenatal exposure to tobacco, alcohol, cannabis and caffeine on birth size and subsequent growth

Maternal use of cigarettes, alcohol, cannabis, and caffeine was established for four time periods; prepregnancy, first trimester, third trimester and average use over pregnancy. The relationship between such usage and growth parameters of offspring followed up from birth to 12 and 24 months of age were examined. Of the soft drugs used, nicotine had the most pronounced effect. After adjustment for other relevant variables, nicotine use prior to and during pregnancy was negatively related to weight and head circumference at birth. Furthermore, third trimester nicotine use was a stronger predictor of decreased weight and head circumference at birth than was first trimester use. The results obtained are consistent with ponderal index (PI) literature suggesting a recovery of growth retardation in infants with a lowered PI. Average consumption of greater than one ounce of absolute alcohol per day was negatively related to birth weight and length. Neither cannabis nor caffeine use had a significant negative effect on any growth parameter.     

Study of serum immunoglobulins in normal pregnancy

Suppression of maternal immune response may be one of the factors contributing to continuation of pregnancy, a state in which the foetus exists as a well tolerated homograft. Studies on serum immunoglobulin levels in pregnancy show varying results. In this study serum immunoglobulin levels of Ig G, Ig A and Ig M were estimated in 75 normal pregnant women, 25 in each trimester. These were compared with a control group of 25 healthy women. A graded significant decrease in Ig G levels was observed throughout the pregnancy. Ig A levels decreased during the first and second trimester of pregnancy. A significant increase in Ig M levels from the first to third trimester was observed.     

Assessing the accuracy of self‐reported smoking status and impact of passive smoke exposure among pregnant Aboriginal and Torres Strait Islander women using cotinine biochemical validation

Introduction and Aims. A significant level of misreport or error occurs during questionnaire‐based assessment of smoking behaviour. Failure to measure environmental tobacco smoke, and participant's inclination to under‐report their smoking raise questions as to the accuracy of assessment. In order to establish an estimation of the possible error associated with such assessment, the accuracy of self‐reported smoking status among a group of pregnant Aboriginal and Torres Strait Islander women was examined. Design and Methods. Women attending two Aboriginal Medical services in Far North Queensland for antenatal care were invited to participate. Women completed an interviewer assisted questionnaire relating to their smoking status and a 24 h diary of their exposure to nicotine and consumption of alcohol. Urine samples were analysed for cotinine using an Enzyme Linked Immunosorbent Assay. Results. Cotinine analysis indicated that 17% of women who reported that they were non‐smokers were likely to have misreported this status, or be exposed to high levels of passive smoke. The only significant predictors of cotinine level were self‐reported nicotine exposure (including passive smoke) and number of cigarettes smoked in the previous 24 h. Other individual and environmental variables had no significant influence on cotinine level using this analysis technique. Discussion and Conclusions. The level of potential error in smoking assessment among this group was substantial. Exposure to environmental tobacco smoke might explain part of this error, but the reasons for misreport can only be speculated. This rate of misclassification should be taken into consideration in routine screening of antenatal women in primary health care.[Gilligan C, Sanson‐Fisher R, Eades S, Wenitong M, Panaretto K, D'Este C. Assessing the accuracy of self‐reported smoking status and impact of passive smoke exposure among pregnant Aboriginal and Torres Strait Islander women using cotinine biochemical validation. Drug Alcohol Rev 2009]     

Nicotine dose-concentration relationship and pregnancy outcomes in rat: biologic plausibility and implications for future research

Cigarette smoke (CS) exposure during pregnancy can lead to profound adverse effects on fetal development. Although CS contains several thousand chemicals, nicotine has been widely used as its surrogate as well as in its own right as a neuroteratogen. The justification for the route and dose of nicotine administration is largely based on inferential data suggesting that nicotine 6 mg/kg/day infused continuously via osmotic mini pumps (OMP) would mimic maternal CS exposure. We provide evidence that 6 mg/kg/day nicotine dose as commonly administered to pregnant rats leads to plasma nicotine concentrations that are 3-10-fold higher than those observed in moderate to heavy smokers and pregnant mothers, respectively. Furthermore, the cumulative daily nicotine dose exceeds by several hundred fold the amount consumed by human heavy smokers. Our study does not support the widely accepted notion that regardless of the nicotine dose, a linear nicotine dose-concentration relationship exists in a steady-state OMP model. We also show that total nicotine clearance increases with advancing pregnancy but no significant change is observed between the 2nd and 3rd trimester. Furthermore, nicotine infusion even at this extremely high dose has little effect on a number of maternal and fetal biologic variables and pregnancy outcome suggesting that CS constituents other than nicotine mediate the fetal growth restriction in infants born to smoking mothers. Our current study has major implications for translational research in developmental toxicology and pharmacotherapy using nicotine replacement treatment as an aid to cessation of cigarette smoking in pregnant mothers.     

Social-environmental factors related to prenatal smoking

Introduction

Cigarette smoking during pregnancy is a significant public health issue that has profound effects on maternal and fetal health. Although many women stop smoking upon pregnancy recognition, a large number continue. Given the higher burden of smoking among low-income women, the focus of this study is to examine the impact of pre-conception social-environmental influences on smoking cessation during the first trimester of pregnancy.

Methods

Pregnant women who presented for prenatal were asked to complete a screening form at their first prenatal appointment. Women who agreed to participate were scheduled for a total of four interviews; a prenatal interview at the end of each trimester and a postnatal interview at 2 months of infant age. The sample for the current report consisted of pregnant women (first trimester) with a partner (N = 316).

Results

After controlling for pre-conception heaviness of smoking, a number of social-environmental factors were associated with smoking during the first trimester. Women were more likely to smoke during the first trimester if their partner was a smoker; however, the presence of other household smokers was not associated with increased risk for smoking. Additionally, women with a greater proportion of friends (but not relatives) who smoked and more frequent exposure to environmental tobacco were more likely to smoke.

Conclusions

This work found differential impacts of the social network on smoking suggesting that understanding relationship type, not simply number of smokers, may be important for smoking cessation efforts. Understanding differences in social network influences on smoking can help to inform interventions.     

Assessment of prenatal smoke exposure by determining nicotine and its metabolites in maternal and neonatal urine

Urine specimens were collected from 75 pregnant women before childbirth and from their newborns within 48 postnatal hours. A high-performance liquid chromatography (HPLC) method was used to determine urinary nicotine and its metabolites, cotinine and trans-3'-hydroxycotinine (OH-cotinine) to objectivise prenatal smoke exposure. Using the sum of nicotine metabolites as a marker, 34 women were classed as not exposed to smoke ( < 15 nmol/l), 18 as passive smokers (15-400 nmol/l), and 23 as active smokers ( > 400 nmol/1). The newborns of active smokers exhibited significantly (P < 0.001) higher nicotine metabolite concentrations than did those of either non-exposed women or passive smokers. A close correlation was found to exist between maternal and neonatal nicotine and cotinine concentrations (r=0.8968 and r=0.9205, respectively). For OH-cotinine, this correlation was particularly close when maternal, but not neonatal, OH - cotinine was adjusted to creatinine (r=0.9792). The neonatal/maternal urine concentration ratios for cotinine and OH-cotinine were noted to not significantly depend on the time of postpartal urine collection. Within the first two postnatal days, the extent of current prenatal smoke exposure attributable to active smoking of the mother was best reflected by the urinary concentrations of cotinine plus OH-cotinine without adjustment to creatinine.     

不同孕期妇女尿碘水平与甲状腺功能关系的调查研究

目的：探讨孕早期、孕中期及孕晚期孕妇尿碘水平与甲状腺功能的关系。方法采用单纯随机抽样法抽取本地区孕妇405例进行调查,孕早期136例,孕中期141例,孕晚期128例,按甲状腺功能是否正常分为甲状腺功能正常组383例,甲状腺功能异常组22例。结果孕早期、孕中期甲状腺功能正常率明显高于孕晚期,甲状腺功能异常率低于孕晚期,差异有统计学意义（P＜0.05）,甲状腺功能正常组孕早期尿碘分级＜100μg/L妇女比例明显低于甲状腺功能异常组孕早期妇女,尿碘分级为100～300μg/L妇女比例明显高于甲状腺异常组孕早期妇女,差异有统计学意义（P＜0.05）。结论尿碘监测对孕早期的孕妇具有重要的意义,建议对尿碘分级＜100μg/L或100～300μg/L的孕妇进行甲状腺功能筛查。     

Metabolism of nicotine by rat liver cytochromes P-450. Assessment utilizing monoclonal antibodies to nicotine and cotinine.

Because of the prevalence of cigarette smoking in the general population and because studies suggest that a large percentage of nicotine is metabolized to cotinine in humans, it is important to study the enzymes responsible for nicotine metabolism. The cytochromes P-450 have long been implicated in the first step in the conversion of nicotine to nicotine delta 1'(5')-iminium ion. We demonstrate here that rat liver P-450IIB1 is able to convert nicotine to cotinine in the presence of cytosol with a Km of 5-7 microM. A constitutive form of P-450 is also implicated in nicotine metabolism, while purified P-450IA1 and P-450IIC6 show no detectable activity. The lack of P-450IA1 activity substantiates work by others who also failed to observe an increase in the efficiency of nicotine metabolism to cotinine by microsomes from rats that had been pretreated with benzanthracene. This result is in contrast to work with purified rabbit liver enzymes, in which P-450IA1 exhibited low but measurable activity. Our results support the notion that nicotine metabolism to cotinine by P-450 enzymes is highly species dependent. Thus, it is unwise in some cases to extrapolate results obtained by animal model study to the possible role of specific forms of the P-450 enzymes in nicotine metabolism in humans.     

Usefulness of salivary trans-3'-hydroxycotinine concentration and trans-3'-hydroxycotinine/cotinine ratio as biomarkers of cigarette smoke in pregnant women

Nicotine is rapidly and extensively metabolized in humans and negatively impacts the developing fetus. The concentrations of nicotine, cotinine, trans-3'-hydroxycotinine (hydroxycotinine), and norcotinine in pregnant smokers' oral fluid were evaluated to determine usefulness as biomarkers of cigarette smoking. Sixteen participants were divided into two groups: eight light smokers (LS) who smoked < or =10 cigarettes/day and eight heavy smokers (HS) who smoked > or =20 cigarettes/day. Oral fluid specimens (n=415) were collected throughout pregnancy and analyzed with solid-phase extraction followed by gas chromatography-mass spectrometry-electron impact selected ion monitoring. Median concentrations of nicotine, cotinine, and hydroxycotinine in oral fluid of LS ranged from 241.1 to 622.0, 80.6 to 387.5, and 14.4 to 117.7 ng/mL and for HS 146.5-1372.2, 66.0-245.8, and 38.3-184.4 ng/mL, respectively. Salivary cotinine and hydroxycotinine concentrations were significantly correlated in LS (r = 0.55, p < 0.01) and HS (r = 0.74, p < 0.01). Ratios of hydroxycotinine/cotinine in oral fluid from pregnant women averaged 0.30 +/- 0.18 (range, 0.07-1.05) for LS and 0.68 +/- 0.25 (range, 0.29-1.83) for HS. Based on these preliminary data, the best ratio to differentiate light from heavy pregnant smokers was 0.41. Salivary hydroxycotinine and cotinine concentrations are both good biomarkers of cigarette smoking. Determining the hydroxycotinine/cotinine ratio may differentiate light from heavy tobacco use and help predict increased fetal tobacco exposure.     

Interindividual differences in nicotine metabolism and genetic polymorphisms of human CYP2A6

Nicotine is widely consumed throughout the world, and exerts a number of physiological effects. After nicotine is absorbed through the lungs by cigarette smoking, it undergoes extensive metabolism in humans. Nicotine is mainly metabolized to cotinine by cytochrome P450 (CYP) 2A6. CYP2A6 can metabolize some pharmaceutical agents such as halothane, valproic acid, and fadrozole, and activate tobacco-specific nitrosamines. There are large interindividual differences in nicotine metabolism, and it has been found that the interindividual differences are attributed to the genetic polymorphisms of CYP2A6 gene. This review describes the techniques for determination of in vivo nicotine metabolism, characteristics of each human CYP2A6 alleles, and ethnic differences. The relationship between CYP2A6 genetic polymorphism and potency of nicotine metabolism, smoking behavior, and cancer risk are extensively reviewed. Finally, the usefulness of nicotine metabolism for phenotyping of CYP2A6 in individuals and implication of the significance of CYP2A6 genetic polymorphism in a clinical perspective are discussed.