Metabolic profile of nicotine in subjects whose CYP2A6 gene is deleted

Yamanaka, Hidetoshi; Nakajima, Miki; Nishimura, Kiyoko; Yoshida, Ryoko; Fukami, Tatsuki; Katoh, Miki; Yokoi, Tsuyoshi

doi:10.1016/j.ejps.2004.04.012

Cited by 79 publications

(81 citation statements)

References 26 publications

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“…As a major metabolic pathway in the periphery, nicotine primarily (ϳ80%) undergoes liver aldehyde oxidation via CYP2A6 to form cotinine in humans (Messina et al, 1997;Yamanaka et al, 2004) and in rats (homolog CYP2B1) (Hammond et al, 1991;Nakayama et al, 1993). There is controversy as to whether cotinine penetrates the BBB from plasma (Halldin et al, 1992;Riah et al, 1998) or whether the detection of cotinine in brain is solely the result of central nicotine metabolism.…”

Section: Discussionmentioning

confidence: 99%

Brain Uptake Kinetics of Nicotine and Cotinine after Chronic Nicotine Exposure

Lockman¹,

McAfee²,

Geldenhuys³

et al. 2005

J Pharmacol Exp Ther

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Blood-brain barrier (BBB) nicotine transfer has been well documented in view of the fact that this alkaloid is a cerebral blood flow marker. However, limited data are available that describe BBB penetration of the major tobacco alkaloids after chronic nicotine exposure. This question needs to be addressed, given long-term nicotine exposure alters both BBB function and morphology. In contrast to nicotine, it has been reported that cotinine (the major nicotine metabolite) does not penetrate the BBB, yet cotinine brain distribution has been well documented after nicotine exposure. Surprisingly, therefore, the literature indirectly suggests that central nervous system cotinine distribution occurs secondarily to nicotine brain metabolism. The aims of the current report are to define BBB transfer of nicotine and cotinine in naive and nicotine-exposed animals. Using an in situ brain perfusion model, we assessed the BBB uptake of 3 H]cotinine BBB transfer is not altered by chronic nicotine exposure. To our knowledge, this is the first report detailing the uptake of nicotine and cotinine after chronic nicotine exposure and quantifying the rate of BBB penetration by cotinine.

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Section: Discussionmentioning

confidence: 99%

Brain Uptake Kinetics of Nicotine and Cotinine after Chronic Nicotine Exposure

Lockman¹,

McAfee²,

Geldenhuys³

et al. 2005

J Pharmacol Exp Ther

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“…We chose this time because it is near the Cmax values of nicotine and cotinine after smoking (Yamanaka et al, 2004). The plasma concentrations of nicotine after one cigarette were 13.7 ng/ml and 15.7 ng/ml, and those of cotinine were 5.1 ng/ml and 17.9 ng/ml (Table 4), suggesting that the subjects had inhaled the cigarette smoke.…”

Section: Smoking One Cigarette Does Not Cause a Dramatic Change In Thmentioning

confidence: 99%

“…The residue was redissolved in 50 µl of the mobile phase, and then a 20 µl portion of the sample was subjected to liquid chromatography/tandem mass spectrometry (LC-MS/MS). The LC-MS/MS condition was described in our previous report (Yamanaka et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Cigarette smoking substantially alters plasma microRNA profiles in healthy subjects

Takahashi

Yokota

Tatsumi

et al. 2013

Toxicology and Applied Pharmacology

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119

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Circulating microRNAs (miRNAs) are receiving attention as potential biomarkers of various diseases, including cancers, chronic obstructive pulmonary disease, and cardiovascular disease. However, it is unknown whether the levels of circulating miRNAs in a healthy subject might vary with external factors in daily life. In this study, we investigated whether cigarette smoking, a habit that has spread throughout the world and is a risk factor for various diseases, affects plasma miRNA profiles. We determined the profiles of 11 smokers and 7 non-smokers by TaqMan MicroRNA array analysis. A larger number of miRNAs were detected in smokers than in non-smokers, and the plasma levels of two thirds of the detected miRNAs (43 miRNAs) were significantly higher in smokers than in non-smokers. A principal component analysis of the plasma miRNA profiles clearly separated smokers and non-smokers. Twenty-four of the miRNAs were previously reported to be potential biomarkers of disease, suggesting the possibility that smoking status might interfere with the diagnosis of disease. Interestingly, we found that quitting smoking altered the plasma miRNA profiles to resemble those of non-smokers. These results suggested that the differences in the plasma miRNA profiles between smokers and non-smokers could be attributed to cigarette smoking. In addition, we found that an acute exposure of ex-smokers to cigarette smoke (smoking one cigarette) did not cause a dramatic change in the plasma miRNA profile. In conclusion, we found that repeated cigarette smoking substantially alters the plasma miRNA profile, interfering with the diagnosis of disease or signaling potential smoking-related diseases.

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“…17) To elucidate the nicotine metabolism in the subjects whose CYP2A6 gene is deleted, the urinary excretion proˆle of nicotine metabolism was determined by a liquid chromatography tandem mass spectrometry (LC-MS W MS) method. 38) In that study, 5 Japanese subjects who were genotyped for the CYP2A6 gene participated. They chewed one piece of nicotine gum, and 24-hr accumulated urine samples were analyzed for nicotine metabolites.…”

Section: Interindividual Dišerences In Cotinine Formation Andmentioning

confidence: 99%

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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Metabolic profile of nicotine in subjects whose CYP2A6 gene is deleted

Cited by 79 publications

References 26 publications

Brain Uptake Kinetics of Nicotine and Cotinine after Chronic Nicotine Exposure

Brain Uptake Kinetics of Nicotine and Cotinine after Chronic Nicotine Exposure

Cigarette smoking substantially alters plasma microRNA profiles in healthy subjects

Interindividual Variability in Nicotine Metabolism: C-Oxidation and Glucuronidation

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