Biomedical subjects

Rachel F Tyndale

Publications and source records attributed to Rachel F Tyndale.

At least 37 records · Page 2Linked to original sources

PubMed2005

Regional and cellular distribution of CYP2E1 in monkey brain and its induction by chronic nicotine.

CYP2E1 is expressed in liver and extrahepatic tissues, including brain. It metabolizes ethanol and other drugs and toxins, such as acetaminophen, chlorzoxazone and tobacco-derived nitrosamines. Hepatic CYP2E1 is inducible by nicotine, and cigarette smoke accelerates chlorzoxazone metabolism. Smokers have higher levels of brain CYP2E1 expression than non-smokers, but the specific regions and cell types which have the higher expression differ from nicotine-induced rat brain. We therefore investigated the expression and distribution of brain CYP2E1 in a non-human primate, the African green monkey, and determined the effect of nicotine treatment. CYP2E1 levels varied among saline-treated monkey brain regions (P < 0.01) and expression was cell-type specific. Chronic nicotine treatment induced CYP2E1 expression in the frontal cortex (1.5-fold, P < 0.05) and cerebellum (1.5-fold, P < 0.01), specifically in cortical pyramidal neurons and cerebellar Purkinje cells but no change was seen in temporal cortex (P = 0.20), hippocampus (P = 0.29), putamen (P = 0.26) and thalamus (P = 0.08). CYP2E1 expression pattern in monkey brain following chronic nicotine treatment is similar to that in smokers, suggesting that nicotine may be the primary component in cigarette smoke that induces CYP2E1. Increased CYP2E1 in brain may contribute to oxidative stress and alter localized metabolism, and resulting pharmacology, of centrally acting drugs metabolized by CYP2E1.

Analysis of Variance↗

PubMed2005

CYP2B6 is expressed in African Green monkey brain and is induced by chronic nicotine treatment.

CYP2B6 is a drug-metabolizing enzyme expressed in human tissues that can activate bupropion (a smoking cessation drug) and tobacco smoke nitrosamines and can inactivate drugs such as nicotine. Smokers have higher brain CYP2B6 protein levels compared to non-smokers but the cause of this elevation is unknown. We investigated the basal expression and the effect of chronic nicotine treatment on CYP2B6 protein in African Green monkey (Cercopithecus aethiops) brain. Basal expression of brain CYP2B6 was strong in specific cells such as the frontal cortical pyramidal cells, the cerebellar Purkinje cells and the neurons in the substantia nigra. Basal CYP2B6 protein levels varied 2.7-fold (non-significant) among 12 brain regions. All monkeys were given a subcutaneous 0.1 mg/kg nicotine test dose prior to treatment and the maximum plasma concentration achieved was 87 +/- 69 ng/ml and the half-life was 2.6 +/- 1.5 h. Monkeys were treated subcutaneously twice daily with nicotine at 0.05 mg/kg for 2 days, 0.15 mg/kg for 2 days followed by 0.3 mg/kg for 18 days (n = 6) or saline (n = 6). Chronic nicotine treatment induced CYP2B6 expression in specific cells such as astrocytes and neurons in the frontal cortex, caudate, thalamus and hippocampus. CYP2B6 protein levels were induced 1.5-fold in the frontal cortex (p < 0.01). Hepatic CYP2B6 expression was not altered by nicotine. In conclusion, CYP2B6 protein is expressed in specific cells in monkey brain and is induced by chronic nicotine treatment which may impact central metabolism of CYP2B6 substrates such as bupropion and nicotine.

Animals↗

PubMed2005

Human CYP2D6 and mouse CYP2Ds: organ distribution in a humanized mouse model.

Polymorphic cytochrome P450 (P450) 2D6 (CYP2D6) metabolizes several classes of therapeutic drugs, endogenous neurochemicals, and toxins. A CYP2D6-humanized transgenic mouse line was previously developed to model CYP2D6-poor and -extensive metabolizer phenotypes. Human CYP2D6 was detected in the liver, kidney, and intestine of these animals. In this study, we investigated further the cellular expression and relative tissue levels of human CYP2D6 in these transgenic mice in liver, intestine, kidney, and brain. In addition, we compared this with the expression of mouse CYP2D enzymes in these organs. In humans, these organs are of interest with respect to P450-mediated drug metabolism, toxicity, and disease. The expression of human CYP2D6 and mouse CYP2D enzymes in humanized and wild-type mice was quantified by immunoblotting and detected at the cellular level by immunocytochemistry. The cell-specific expression of human CYP2D6 in liver, kidney, and intestine in humanized mice was similar to that reported in humans. The expression patterns of mouse CYP2D proteins were similar to those in humans in liver and kidney but substantially different in intestine. Human CYP2D6 was not detected in brain of transgenic mice. Mouse CYP2D proteins were detected in brain, allowing, for the first time, a direct comparison of CYP2D expression among mouse, rat, and human brain. This transgenic mouse model is useful for investigating CYP2D6-mediated metabolism in liver, kidney, and especially the intestine, where expression patterns demonstrated substantial species differences.

Animals↗

PubMed2005

Implications of CYP2A6 genetic variation for smoking behaviors and nicotine dependence.

Nicotine is the primary addictive compound in tobacco smoke. In this review we summarize nicotine dependence and the genetics of smoking in brief before focusing on cytochrome P450 (CYP) 2A6. In humans nicotine is mainly inactivated to cotinine and CYP2A6 mediates approximately 90% of this conversion. Some, but not all, studies suggest that genetic variation in CYP2A6 may play a role in smoking. We review some of the recent findings on the influence of CYP2A6 genetic polymorphisms on nicotine kinetics, smoking behaviors, and how the gene appears to exert differential effects during various stages of smoking (eg, initiation, conversion to dependence, amount smoked during dependence, and quitting). These new findings will be put in the context of the discrepancies found in the literature. Implications of these recent findings on current and novel treatment approaches for smoking cessation and tobacco-related lung cancer will also be discussed.

Animals↗

PubMed2005

Genetic influences on smoking: a brief review.

Smoking is a complex behavior influenced by environ-mental and genetic factors. A number of twin studies demonstrate genetic influences on multiple aspects of smoking including initiation, dependence, continuation, amount consumed, and cessation. It is likely that this genetic risk involves a complex interaction between multiple genes in different biologic pathways. These may include genes involved in the general aspect of dependence (eg, genes within the dopaminergic system) and those more specific to nicotine dependence (eg, genes encoding nicotinic acetylcholine receptors and nicotine-metabolizing enzymes). Genome-wide linkage analyses and gene association studies provide approaches for identifying these genes. This review provides a brief highlight of data from some of the candidate gene association studies and discusses some of the discrepancies found in the literature. In addition, the authors have reviewed some recent studies examining how genetic variations in drug-metabolizing enzymes and drug targets can influence the response to treatment with drugs such as bupropion and nicotine.These latter studies provide the potential for maximizing treatment efficacy by individualizing the type, dosage, and duration of the treatment based on an individual's genotype/phenotype. Significant advances have been made in understanding the genetic contribution to smoking behaviors. These and future studies will provide potential directions for novel prevention and treatment strategies.

Antidepressive Agents, Second-Generation↗

PubMed2005

Nicotine metabolism: the impact of CYP2A6 on estimates of additive genetic influence.

To conduct a pharmacogenetic investigation of nicotine metabolism in twins. One hundred and thirty nine twin pairs [110 monozygotic (MZ) and 29 dizygotic (DZ)] underwent a 30-min infusion of stable isotope-labelled nicotine and its major metabolite, cotinine, followed by an 8-h in-hospital stay. Blood and urine samples were taken at regular intervals for analysis of nicotine, cotinine and metabolites by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry and subsequent characterization of pharmacokinetic and metabolism phenotypes. DNA was genotyped to confirm zygosity and for variation in the gene for the primary enzyme involved in nicotine metabolism, CYP2A6 (alleles tested: *1, *1x2, *2, *4, *7, *9 and *12). Univariate biometric analyses quantified genetic and environmental influences on each pharmacokinetic measure in the presence and absence of covariates, including measured CYP2A6 genotype. The best-fitting model identified a substantial amount of variation in the weight-adjusted rate of total clearance of nicotine attributable to additive genetic influences [59.4%, 95% confidence interval (CI)=44.7-70.7]. The majority of variation in the clearance of nicotine via the cotinine pathway was similarly genetically influenced (60.8%, 95% CI=46.9-71.5). Heritability estimates were reduced to 54.2% and 51.8%, respectively, but remained substantial after taking into account the effect of variation in CYP2A6 genotype. These results suggest the involvement of additional genetic factors (e.g. uncharacterized or novel CYP2A6 alleles as well as other genes in the metabolic pathway) that remain to be identified.

Adolescent↗

PubMed2005

Ethnic variation in CYP2A67, CYP2A68 and CYP2A6*10 as assessed with a novel haplotyping method.

Cytochrome P450 2A6 is the main human nicotine metabolizing enzyme coded for by a highly polymorphic gene, CYP2A6. CYP2A6*7, CYP2A6*8 and CYP2A6*10 are variant alleles common to Asian ethnicities. The CYP2A6*7 and CYP2A6*8 alleles each contain a non-synonymous single nucleotide polymorphism (SNP) 6558T>C and 6600G>T, respectively, whereas the CYP2A6*10 haplotype allele contains both. We have developed the first haplotyping assay; it can unambiguously distinguish the CYP2A6*7, CYP2A6*8 and CYP2A6*10 alleles. The allele frequencies of these three variants were assessed using the novel haplotyping assay in Chinese-Canadian (n=112), Chinese-American (n=221), Taiwanese (n=319), Korean-American (n=207) and Japanese-Canadian (n=64) populations, as well as in Caucasian (n=110) and African-Canadian (n=113) populations. Our new method demonstrated higher frequencies of CYP2A6*7 and CYP2A6*10, and a lower frequency of CYP2A6*8 in Asian populations, but no significant change of allele frequencies in Caucasian or African-Canadian populations.

Africa↗

PubMed2004

Nicotine physical dependence and tolerance in the mouse following chronic oral administration.

RATIONALE: Although nicotine dependence and tolerance develop in rats, few studies have examined these processes in the mouse. Establishing such mouse models would eventually allow for an examination of the role of specific nicotinic receptor subtypes in mediating these processes (i.e. through the use of receptor knockouts). OBJECTIVES: The goals of the present study were to establish mouse models of nicotine dependence and tolerance. METHODS: Mice were chronically exposed to nicotine (0-200 mug/ml) in their drinking solution and assayed for plasma nicotine and cotinine levels, withdrawal signs following nicotine cessation (spontaneous withdrawal) or nicotinic antagonist administration (precipitated withdrawal), or nicotine tolerance. Dependence assays included somatic sign observations (paw tremors, backing and head shakes), tail-flick, plantar stimulation, elevated plus-maze and spontaneous activity. Tolerance was assayed using tail-flick, hot-plate and body temperature tests. RESULTS: Plasma nicotine and cotinine levels were elevated during oral nicotine exposure (15.85 ng/ml and 538.00 ng/ml, respectively) and quickly declined following nicotine cessation (<1 ng/ml and <2 ng/ml, respectively), providing evidence that the oral route was pharmacologically relevant. Nicotine withdrawal increased numbers of somatic signs (spontaneous and mecamylamine-precipitated withdrawal) and/or hyperalgesia (spontaneous withdrawal only). Chronic nicotine exposure also produced tolerance, as indicated by reduced responsivity to acute nicotine in assays of analgesia and hypothermia. CONCLUSIONS: These results indicate that chronic oral nicotine produces dependence and tolerance in the mouse. Further, nicotine dependence may be mediated by multiple nicotinic receptor subtypes, since specific nicotinic receptor antagonists failed to precipitate withdrawal.

Administration, Oral↗

PubMed2004

Case-control study of genotypes in multiple chemical sensitivity: CYP2D6, NAT1, NAT2, PON1, PON2 and MTHFR.

BACKGROUND: Impaired metabolism of toxic chemicals is a postulated mechanism underlying multiple chemical sensitivity (MCS). Because genetic variation alters the rate of chemical metabolism, this study was designed to determine if MCS cases differed from controls for genetic polymorphisms in drug-metabolizing enzymes. METHODS: Female Caucasian participants (203 cases and 162 controls) were drawn from a larger case-control study based on a reproducible and validated case definition. Common polymorphisms for CYP2D6, NAT1, NAT2, PON1, and PON2 were genotyped. RESULTS: Comparing cases and controls, significant differences were found in genotype distributions for CYP2D6 (P = 0.02) and NAT2 (P = 0.03). Compared with the referent homozygous inactive (CYP2D6) or slow (NAT2) metabolizers, the odds for being CYP2D6 homozygous active (OR = 3.36, P = 0.01) and NAT2 rapid (OR = 4.14, P = 0.01) were significantly higher in cases than controls. The odds for being heterozygous for PON1-55 (OR = 2.05, P = 0.04) and PON1-192 (OR = 1.57, P = 0.04) were also significantly higher in cases. CONCLUSIONS: A genetic predisposition for MCS may involve altered biotransformation of environmental chemicals. The CYP2D6 enzyme activates and inactivates toxins; the NAT2 enzyme bioactivates arylamines to protein-binding metabolites. A gene-gene interaction between CYP2D6 and NAT2 suggested that rapid metabolism for both enzymes may confer substantially elevated risk (OR = 18.7, P = 0.002). Our finding parallels others' observation of a link between PON1 heterozygosity and neurological symptoms in Gulf War syndrome. This first demonstration of genetic variation in drug-metabolizing enzymes in association with MCS requires replication. However, it suggests new research directions on genetically variable toxin pathways that might be important in MCS.

Adult↗

PubMed2004

Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity.

BACKGROUND: Nicotine and a variety of other drugs and toxins are metabolized by cytochrome P450 (CYP) 2A6. Our objective was to evaluate the use of oral nicotine with measurement of the trans-3'-hydroxycotinine (3HC)/cotinine (COT) metabolite ratio as a noninvasive probe of CYP2A6 activity. METHODS: Sixty-two healthy volunteers received an oral solution of deuterium-labeled nicotine (2 mg) and its metabolite cotinine (10 mg). Plasma nicotine and plasma and saliva cotinine and 3HC concentrations were measured over time. RESULTS: The 3HC/COT ratio derived from deuterium-labeled cotinine, measured in either plasma (2-8 hours after administration) or saliva (at 6 hours), was strongly correlated with the oral clearance of nicotine (r = 0.76-0.83, depending on the time of measurement). The 6-hour 3HC/COT ratio from nicotine derived from tobacco in 14 smokers was highly correlated with the ratio derived from deuterium-labeled nicotine (r = 0.88) and was also highly correlated with the oral clearance of nicotine (r = 0.90). Two subjects homozygous for inactive CYP2A6 alleles produced no 3HC, confirming the specificity of the metabolite ratio. The 3HC/COT ratio was also highly correlated with the clearance and half-life of cotinine, consistent with the fact that cotinine is also primarily metabolized by CYP2A6. CONCLUSIONS: The 3HC/COT ratio derived from nicotine either administered as a probe drug or from tobacco use, measured in either plasma or saliva, is highly correlated with the oral clearance of nicotine. The ratio appears to be a useful noninvasive marker of the rate of nicotine metabolism (which is important in studying nicotine addiction and smoking behavior), as well as a general marker of CYP2A6 activity (which is important in studying drug and toxin metabolism).

Adult↗

PubMed2004

Evidence of association between smoking and alpha7 nicotinic receptor subunit gene in schizophrenia patients.

A number of studies have suggested that the alpha-7-nicotinic receptor D15S1360 polymorphism is associated with schizophrenia and a deficiency in the normal inhibition of the P50 auditory-evoked response. Schizophrenia patients and some of their unaffected relatives show a failure of inhibition in their 50-ms response to the second of a pair of tones. Biochemical studies have suggested that the alpha7 nicotinic acetylcholine receptor is involved in this sensory gating deficit. Furthermore, high-dose nicotine transiently normalizes the abnormality in P50 inhibition in schizophrenic patients and in their relatives. Schizophrenic patients are unusually heavy smokers, and up to 85% of hospitalized schizophrenic patients smoke. This rate is three times higher than the general population, and may represent an attempt to self-medicate through this pathophysiologic mechanism. Despite schizophrenics' extremely heavy nicotine use, nicotinic receptor genes have not been previously investigated in relation to smoking in schizophrenia. In this study, we hypothesized that the D15S1360 marker is associated with smoking in patients with schizophrenia. We found an association between the homozygous 113 bp allele and smoking risk (chi2=10.37, 3 df, p=0.015). Although this novel finding requires replication, it suggests that further study into the relationship between schizophrenia and nicotine system genes is warranted.

Adult↗

PubMed2004

The unique regulation of brain cytochrome P450 2 (CYP2) family enzymes by drugs and genetics.

Cytochrome P450 (CYP) enzymes in the brain may have a role in the activation or inactivation of centrally acting drugs, in the metabolism of endogenous compounds, and in the generation of damaging toxic metabolites and/or oxygen stress. CYPs are distributed unevenly among brain regions, and are found in neurons, glial cells and at the blood-brain interface. They have been observed in mitochondrial membranes, in neuronal processes and in the plasma membrane, as well as in endoplastic reticulum. Brain CYPs are inducible by many common hepatic inducers, however many compounds affect liver and brain CYP expression differently, and some CYPs which are constitutively expressed in liver are inducible in brain. CYP induction is isozyme-, brain region-, cell type- and inducer-specific. While it is unlikely that brain CYPs contribute to overall clearance of xenobiotics, their punctate, region- and cell-specific expression suggests that CNS CYPs may create micro-environments in the brain with differing drug and metabolite levels (not detected or predicted by plasma drug monitoring). Coupled with the sensitivity of CNS CYPs to induction, this may in part account for inter-individual variation in response to centrally acting drugs and neurotoxins, and may have implications for individual variation in receptor adaptation and cross-tolerance to different drugs. In addition, genetic variation in brain CYPs, depending on the type of polymorphism (structural versus regulatory), will alter enzyme activity. These aspects of brain CYP expression regulation and genetic influences are illustrated in this review using mRNA, protein, and enzyme activity data for CYP2D1/6, CYP2E1 and CYP2B1/6 in rat and human brain. The role of CYP-mediated metabolism in the brain, a highly heterogeneous and complex organ, is a new and relatively unexplored field of scientific enquiry. It holds promise for furthering our undestanding of inter-individual variability in response to centrally acting drugs as well as risk for neurological diseases and pathogies.

Animals↗

PubMed2004

Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians.

Genetically variable CYP2A6 is the primary enzyme that inactivates nicotine to cotinine. Our objective was to investigate allele frequencies among five ethnic groups and to investigate the relationship between genetically slow nicotine metabolic inactivation and smoking status, cigarette consumption, age of first smoking and duration of smoking. Chinese, Japanese, Canadian Native Indian, African-North American and Caucasian DNA samples were assessed for CYP2A6 allelic frequencies (CYP2A6*1B-*12,*1x2). Adult Caucasian non-smokers (n = 224) (1-99 cigarettes/lifetime) and smokers (n = 375) (> or = 100 cigarettes/lifetime) were assessed for demographics, tobacco/drug use history and DSM-IV dependence and genotyped for CYP2A6 alleles associated with decreased nicotine metabolism (CYP2A6*2, CYP2A6*4, CYP2A6*9, CYP2A6*12). CYP2A6 allele frequencies varied substantially among the ethnic groups. The proportion of Caucasian slow nicotine inactivators was significantly lower in current, DSM-IV dependent smokers compared to non-smokers [7.0% and 12.5%, respectively, P = 0.03, odds ratio (OR) = 0.52; 95% confidence interval (CI) 0.29-0.95]; non-dependent smokers showed similar results. Daily cigarette consumption (cigarettes/day) was significantly (P = 0.003) lower for slow (21.3; 95% CI 17.4-25.2) compared to normal inactivators (28.2; 95% CI 26.4-29.9); this was observed only in DSM-IV dependent smokers. Slow inactivators had a significantly (P = 0.03) lower age of first smoking compared to normal inactivators (13.0 years of age; 95% CI 12.1-14.0 versus 14.2; 95% CI 13.8-14.6), and a trend towards smoking for a shorter duration. This study demonstrates that slow nicotine inactivators are less likely to be adult smokers (dependent or non-dependent). Slow inactivators also smoked fewer cigarettes per day and had an earlier age of first smoking (only dependent smokers).

Adult↗

PubMed2004

Pharmacogenetics of nicotine metabolism in twins: methods and procedures.

This article describes a pharmacogenetic investigation of nicotine metabolism in twins. One hundred and thirty-nine twin pairs (110 monozygotic and 29 dizygotic) were recruited and assessed for smoking status, zygosity, and health conditions known or suspected to affect drug metabolism. Participants underwent a 30-minute infusion of stable isotope-labeled nicotine and its major metabolite, cotinine, followed by an 8-hour in-hospital stay. Blood and urine samples were taken at regular intervals for analysis of nicotine, cotinine, and metabolites by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry and subsequent characterization of pharmacokinetic phenotypes. DNA was genotyped to confirm zygosity and for variation in the primary gene involved in nicotine metabolism, CYP2A6. Univariate and multivariate biometric analyses planned for the future will determine genetic and environmental influences on each pharmacokinetic measure individually and in combination with each other, and in the presence and absence of covariates, including measured genotype. When the analyses are completed, this study will result in a more complete characterization of the impact of genetic and environmental influences on nicotine and cotinine metabolic pathways than has heretofore been reported. The approach taken, with its use of a quantitative model of nicotine metabolism, highly refined metabolic phenotypes, measured genotype, and advanced tools for biometric genetic analysis, provides a model for the use of twins in next-generation studies of complex drug-metabolism phenotypes.

Adult↗

PubMed2003

Decreasing smoking behaviour and risk through CYP2A6 inhibition.

The consequences of tobacco dependence are both health related and economic. Novel treatment approaches are needed to offer alternatives to patients and to improve treatment outcomes. We review concepts and selected recent discoveries in the area of treatment, with a specific orientation towards drug development. Current treatments are outlined and we highlight new strategies that are based on the manipulation of cytochrome P450 2A6 (CYP2A6) activity, which is responsible for the metabolism of nicotine. The clinical implications of CYP2A6 polymorphisms have been linked to a decreased risk of tobacco dependence, a decrease in number of cigarettes smoked and reduced risk of tobacco-related cancers. Further, we discuss a range of models for proof-of-concept studies for new treatments to alleviate tobacco dependence

Aryl Hydrocarbon Hydroxylases↗

PubMed2003

Rat hepatic CYP2E1 is induced by very low nicotine doses: an investigation of induction, time course, dose response, and mechanism.

CYP2E1 is an ethanol- and drug-metabolizing enzyme that can also activate procarcinogens and hepatotoxicants and generate reactive oxygen species; it has been implicated in the pathogenesis of liver diseases and cancer. Cigarette smoke increases CYP2E1 activity in rodents and in humans and we have shown that nicotine (0.1-1.0 mg/kg s.c. x 7 days) increases CYP2E1 protein and activity in the rat liver. In the current study, we have shown that the induction peaks at 4 h postnicotine (1 mg/kg s.c. x 7 days) treatment and recovers within 24 h. No induction was observed after a single injection, and 18 days of treatment did not increase the levels beyond that found at 7 days. We found that CYP2E1 is induced by very low doses of chronic (x 7 days) nicotine with an ED50 value of 0.01 mg/kg s.c.; 0.01 mg/kg in a rat model results in peak cotinine levels (nicotine metabolite) similar to those found in people exposed to environmental tobacco smoke (passive smokers; 2-7 ng/ml). Previously, we have shown no change in CYP2E1 mRNA, and our current mechanistic study indicates that nicotine does not regulate CYP2E1 expression by protein stabilization. We postulated that a nicotine metabolite could be causing the induction but found that cotinine (1 mg/kg x 7 days) did not increase CYP2E1. Our findings indicate that nicotine increases CYP2E1 at very low doses and may enhance CYP2E1-related toxicity in smokers, passive smokers, and people treated with nicotine (e.g., smokers, patients with Alzheimer's disease, ulcerative colitis or Parkinson's disease).

Animals↗

PubMed2003

Induction of nicotine-metabolizing CYP2B1 by ethanol and ethanol-metabolizing CYP2E1 by nicotine: summary and implications.

Alcohol and tobacco are frequently co-abused. Increased alcohol use and alcoholism are associated with smoking, and vice versa. Functional and/or metabolic cross-tolerance may contribute to this occurrence. This review summarizes recent studies published from our laboratory focusing on metabolic aspects of tolerance, which demonstrate that in rat, subchronic, behaviourally relevant doses of ethanol induce hepatic nicotine-metabolizing cytochrome P450 (CYP) 2B1, and that subchronically administered nicotine, at behaviourally relevant doses, induces hepatic ethanol-metabolizing CYP2E1. Increased CYP2B1 protein, mRNA and CYP2B1-mediated nicotine metabolism was observed following ethanol treatments. CYP2E1 protein and activity were induced by nicotine, but no changes were seen in levels of CYP2E1 mRNA. These data indicate that metabolic cross-tolerance may occur between nicotine and ethanol, suggesting that nicotine use may increase the elimination of ethanol, and ethanol use may increase the elimination of nicotine. Other implications, such as altered pharmacology and toxicology of drugs metabolized by these enzymes, as well as changes in pro-carcinogen and pro-toxin activation are also discussed.

Alcohol Drinking↗

PubMed2003

Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain.

CYP2B6 metabolizes drugs such as nicotine and bupropion, and many toxins and carcinogens. Nicotine induces CYP2B1 in rat brain and in humans polymorphic variation in CYP2B6 affects smoking cessation rates. The aim of this study was to compare CYP2B6 expression in brains of human smokers and non-smokers and alcoholics and non-alcoholics (n=26). CYP2B6 expression was brain region-specific, and was observed in both neurons and astrocytes. CYP2B6 levels were higher in brains of smokers and alcoholics, particularly in cerebellar Purkinje cells and hippocampal pyramidal neurons, cells known to be damaged in alcoholics. Significantly more (p<0.05) CYP2B6 protein was seen in four brain regions of smoking alcoholics compared to non-smoking non-alcoholics: hippocampus (5.8-fold), caudate nucleus (3.3-fold), putamen (3.0-fold) and cerebellar hemisphere (1.6-fold). The genetic variant C1459T (R487C) has been associated with reduced hepatic enzyme levels, stability and activity. Preliminary genotyping of this small sample (n=24) suggested that individuals with the CC genotype had higher brain CYP2B6 than those with the CT or TT genotype. Higher brain CYP2B6 activity in smokers and alcoholics may cause altered sensitivity to centrally acting drugs, increased susceptibility to neurotoxins and carcinogenic xenobiotics and contribute to central tolerance to nicotine.

Adolescent↗