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Rachel F Tyndale

Publications and source records attributed to Rachel F Tyndale.

At least 55 records · Page 3Linked to original sources
PubMed2003

Nicotine-dependence symptoms are associated with smoking frequency in adolescents.

BACKGROUND: Although many sociodemographic and psychosocial factors have been identified as related to adolescent smoking, few studies have examined the role of nicotine-dependence (ND) symptoms. The objective was to study the association between ND symptoms and smoking status among adolescents in the early stages of the smoking onset process. METHODS: The McGill University Study on the Natural History of Nicotine Dependence is an ongoing 6-year prospective investigation of the natural history of ND among 1267 grade 7 students in ten Montreal high schools. The baseline response was 55.4%. Subjects for this cross-sectional analysis of baseline data, collected in 1999, included 241 past 3-month smokers (mean age [SD]=13.0+/-0.7 years at baseline). ND symptoms were measured in five indicators, including a measure based on the criteria for tobacco dependence in the International Classification of Diseases-10th Revision (ICD-10), the Hooked on Nicotine Checklist, and three symptom clusters (withdrawal, self-medication, and ND/cravings symptoms). The association between ND symptom indicators and each of sporadic, monthly, weekly, and daily smoking relative to less frequent smoking was investigated in multiple logistic regression analysis. RESULTS: Despite low cigarette exposure, 16.6% (95% confidence interval [CI], 11.9%-21.3%) of past 3-month smokers were tobacco dependent. The proportion increased from 0%, 3.1% (95% CI, 0.0%-9.2%), and 4.6% (95% CI, 0.2%-9.0%) among triers, sporadic smokers, and monthly smokers, respectively, to 19.4% (95% CI, 5.5%-33.3%) and 65.9% (95% CI, 51.9%-79.9%) among weekly and daily smokers, respectively. ND/cravings consistently distinguished each smoking category from less frequent smokers; the odds ratios (95% CI) for ND/cravings symptoms were 1.16 (0.99-1.35) in sporadic smokers; 1.17 (1.06-1.29) in monthly smokers; 1.34 (1.19-1.50) in weekly smokers; and 1.39 (1.22-1.59) in daily smokers. CONCLUSIONS: These data challenge current smoking onset models, which suggest that ND develops only after several years of heavy or daily smoking. ND symptoms are associated, at least cross-sectionally, with increased smoking in adolescents. To increase the likelihood of being effective, tobacco-control programs for children and adolescents will need to take early ND symptoms into account.

Adolescent↗
PubMed2003

Brain CYP2E1 is induced by nicotine and ethanol in rat and is higher in smokers and alcoholics.

1. Ethanol and nicotine are commonly coabused drugs. Cytochrome P450 2E1 (CYP2E1) metabolizes ethanol and bioactivates tobacco-derived procarcinogens. Ethanol and nicotine can induce hepatic CYP2E1 and we hypothesized that both centrally active drugs could also induce CYP2E1 within the brain. 2. Male rats were treated with saline, ethanol (3.0 g kg(-1) by gavage) or nicotine (1.0 mg kg(-1) s.c.) for 7 days. Ethanol treatment significantly increased CYP2E1 in olfactory bulbs (1.7-fold), frontal cortex (2.0-fold), hippocampus (1.9-fold) and cerebellum (1.8-fold), while nicotine induced CYP2E1 in olfactory bulbs (2.3-fold), frontal cortex (3.0-fold), olfactory tubercle (3.1-fold), cerebellum (2.5-fold) and brainstem (2.0-fold). Immunocytochemical analysis revealed that the induction was cell-type specific. 3. Consistent with the increased CYP2E1 found in rat brain following drug treatments, brains from alcoholics and alcoholic smokers showed greater staining of granular cells of the dentate gyrus and the pyramidal cells of CA2 and CA3 hippocampal regions as well as of cerebellar Purkinje cells compared to nonalcoholic nonsmokers. Moreover, greater CYP2E1 immunoreactivity was observed in the frontal cortices in the alcoholic smokers in comparison to nonalcoholic nonsmokers and alcoholic nonsmokers. 4 To investigate if nicotine could contribute to the increased CYP2E1 observed in alcoholic smokers, we treated human neuroblastoma IMR-32 cells in culture and found significantly higher CYP2E1 immunostaining in nicotine-treated cells (0.1-10 nM). 5. CYP2E1 induction in the brain, by ethanol or nicotine, may influence the central effects of ethanol and the development of nervous tissue pathologies observed in alcoholics and smokers.

Adult↗
PubMed2003

Genetics of alcohol and tobacco use in humans.

The field of genetics holds great promise for furthering our understanding of the etiology of drug dependence and for identifying novel targets for treatment. Genetic studies utilizing twins and families have demonstrated a considerable role for genetics in nicotine and/or alcohol dependence. Risk for alcoholism or nicotine dependence is likely to be the result of a large number of genes, each contributing a small fraction of the overall risk. While this review will focus on studies in humans, many of the candidate genes for human nicotine and alcohol dependence listed here were originally postulated to be important, based on data from animal studies. The review will briefly summarize the results from twin and adoption studies that provide estimations of heritability, the results from chromosomal linkage studies that identify regions of chromosomes that may contain relevant genes, and the results of candidate gene studies. For each topic the data will be presented for nicotine dependence, alcohol dependence, and for nicotine and alcohol dependence together. In addition, each section will review briefly some of the confounding issues in the specific type of approach utilized.

Adoption↗
PubMed2003

The effect of methoxsalen on nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in vivo.

Nicotine is metabolized to the inactive metabolite cotinine by cytochrome P450 2A6. NNK, or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, is a potent procarcinogen shown to be activated to a reactive mutagenic metabolite by the enzyme CYP2A6. We studied the effect of inhibiting CYP2A6 on smoking behavior and metabolism of the procarcinogen NNK. In study 1, abstinent smokers (n=7) received methoxsalen (a potent CYP2A6 inhibitor), 30-50 mg orally, one-half hour before three subcutaneous nicotine injections (31 microg/kg) were given at hourly intervals. Methoxsalen increased mean plasma nicotine by 47% (p<.01) and mean nicotine area under the curve (AUC) by 63% (p<.0001); and decreased nicotine clearance by 39% (p<.0001), relative to placebo. In study 2, smokers (n=11) were told to maintain their same number of cigarettes smoked while receiving methoxsalen, 10 mg orally three times daily for 3 days. On day 3 of methoxsalen treatment, a 29% increase in plasma nicotine/expired-air CO (an index of smoke exposure) (p=0.03) was observed. Urinary levels of trans 3'-hydroxycotinine (metabolized by CYP2A6 from cotinine) also were decreased (p<.0001), and significantly more NNK was metabolized to the inactive NNAL-glucuronide (1.04+/-0.54 pmol/mg on day 1 to 1.37+/-0.74 pmol/mg on day 4, p<.01) relative to placebo. Thus, treatment with the CYP2A6 inhibitor methoxsalen in vivo increases the routing of NNK to the inactive NNAL-glucuronide and decreases smoking. CYP2A6 inhibition may have potential as an exposure reduction or cessation strategy in tobacco dependence.

Administration, Oral↗
PubMed2003

CYP2E1*1D regulatory polymorphism: association with alcohol and nicotine dependence.

OBJECTIVE: CYP2E1 bioactivates environmental protoxins and metabolizes alcohol. CYP2E1 is induced by alcohol and cigarette smoking and may contribute to metabolic tolerance in alcoholics. The CYP2E1*1D polymorphism has been associated with greater CYP2E1 inducibility. One objective was to determine the frequency of the variant allele in eight ethnic groups. Further, the Canadian Native Indian, South-east Asian Canadian and Caucasian Canadian groups were stratified by alcohol and nicotine dependence (as measured by DSM-IV criteria) to examine the potential association of CYP2E1*1D with drug dependence. RESULTS AND CONCLUSIONS: We found a significantly greater frequency of the CYP2E1*1D allele among Indo-Asian Canadians (0.31), Chinese Canadians (0.19), Taiwanese (0.20), Japanese Canadians (0.18), African Americans (0.13), African Canadians (0.10) and Canadian Native Indians (0.09) compared to Caucasian Canadians (0.02). Although the power of the association study was low among some subgroups, the CYP2E1*1D genotype (subjects with at least one variant allele) was associated with alcohol as well as nicotine dependence. Specifically, Canadian Native Indians dependent on nicotine alone or alcohol alone exhibited significantly greater CYP2E1*1D frequencies compared to non-drug dependent controls, while the variant frequency among Southeast Asians dependent on nicotine was greater than their non-drug dependent counterparts. We also found that CYP2E1*1D genotype was associated with significantly greater 3-hydroxycotinine per cigarette in African Americans. The variable frequency of CYP2E1*1D among ethnic groups suggests a greater risk for diseases putatively related to CYP2E1 in some non-Caucasian ethnic groups. The association of CYP2E1*1D with alcohol and nicotine dependence suggests that CYP2E1 may contribute to the development of these dependencies.

Alcoholism↗
PubMed2003

Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro.

Buprenorphine is a thebaine derivative used in the treatment of heroin and other opiate addictions. In this study, the selective probe reactions for each of the major hepatic cytochromes P450 (P450s) were used to evaluate the effect of buprenorphine and its main metabolite norbuprenorphine on the activity of these P450s. The index reactions used were CYP1A2 (phenacetin O-deethylation), CYP2A6 (coumarin 7-hydroxylation), CYP2C9 (diclofenac 4'-hydroxylation), CYP2C19 (omeprazole 5-hydrxoylation), CYP2D6 (dextromethorphan O-demethylation), CYP2B6 (7-ethoxy-4-trifluoromethyl-coumarin 7-deethylation), CYP2E1 (chlorzoxazone 6-hydroxylation), and CYP3A4 (omeprazole sulfoxidation). Buprenorphine exhibited potent, competitive inhibition of CYP2D6 (Ki 10 +/- 2 microM and 1.8 +/- 0.2 microM) and CYP3A4 (Ki 40 +/- 1.6 microM and 19 +/- 1.2 microM) in microsomes from human liver and cDNA-expressing lymphoblasts, respectively. Compared with buprenorphine, norbuprenorphine demonstrated a lower inhibitory potency with CYP2D6 (22.4% inhibition at 20 microM norbuprenorphine) and CYP3A4 (13.6% inhibition at 20 microM) in microsomes from human cDNA-expressing lymphoblast cells. Furthermore, buprenorphine was shown to be a substrate of CYP2D6 (Km = 600 microM; Vmax = 0.40 nmol/min/mg protein) and CYP3A4 (Km = 36 microM; Vmax = 0.19 nmol/min/mg protein). The present in vitro study suggests that buprenorphine and its major metabolite norbuprenorphine are inhibitors of CYP2D6 and CYP3A4; however, at therapeutic concentrations they are not predicted to cause potentially clinically important drug interactions with other drugs metabolized by major hepatic P450s.

Buprenorphine↗
PubMed2003

Down-regulation of hepatic nicotine metabolism and a CYP2A6-like enzyme in African green monkeys after long-term nicotine administration.

Nicotine metabolism is decreased in smokers compared with nonsmokers, but the mechanism(s) responsible for the slower metabolism are unknown. Nicotine is inactivated to cotinine by CYP2A6 in human liver [nicotine C-oxidation (NCO)]. CYP2B6 also metabolizes nicotine to cotinine but with lower affinity than CYP2A6. To evaluate the effects of long-term nicotine treatment on hepatic levels of CYP2A6 and CYP2B6, and nicotine metabolism, an African green monkey (AGM) model was developed. As in humans, approximately 80 to 90% of in vitro hepatic NCO is mediated by a CYP2A6-like protein (CYP2A6agm) in this species, as determined by inhibition studies. Male AGM (n = 6 per group) were treated for 3 weeks with nicotine (s.c., 0.3 mg/kg, b.i.d.), phenobarbital (oral, 20 mg/kg, as a positive control for P450 induction), and/or saline (s.c., b.i.d.). Immunoblotting demonstrated a 59% decrease (p < 0.05) in hepatic CYP2A6agm protein in nicotine-treated animals. A CYP2B6-like protein (CYP2B6agm) was modestly and insignificantly decreased (14%, p = 0.11). In vitro NCO was decreased by 41% in the nicotine-treated group (p < 0.05), mediated by a decrease in CYP2A6agm, as demonstrated using inhibitory antibodies. CYP2A6agm mRNA (33%, P < or = 0.05) and CYP2B6agm (35%, p < 0.01) mRNA were also significantly decreased in the nicotine-treated group. Phenobarbital-treated animals demonstrated an increase in CYP2B6agm (650%, p < 0.001), but not CYP2A6agm (20%, p = 0.49). NCO was increased in the phenobarbital-treated group (55%, p < 0.05) by an increase in CYP2B6agm-mediated NCO. Consistent with the slower nicotine metabolism observed in smokers, nicotine may decrease its own metabolism in primates by decreasing the expression of the primary nicotine-metabolizing enzyme CYP2A6.

Animals↗
PubMed2002

CYP2A6 genetic variation and potential consequences.

Human cytochrome P450 2A6 (CYP2A6) has been shown to have large interindividual and interethnic variability in levels of expression and activity. This is thought to be largely due to genetic polymorphisms. In recent years, 13 genetic variants (CYP2A6*1-*11 and the gene duplication, *1 x 2) of CYP2A6 have been identified and a number of these have been shown to result in altered CYP2A6 enzyme activity. For example, there are alleles which result in variants that are in inactive (e.g. due to a gene deletion), have decreased activity (e.g. altered enzyme structure or transcriptional activity) or have increased activity (e.g. due to gene duplications). The resulting interindividual variation in metabolic activity may affect the metabolism of CYP2A6 substrates including nicotine, cotinine (the major metabolite of nicotine), several tobacco-specific procarcinogens, coumarin and many toxins. The frequencies of the CYP2A6 alleles vary considerably among different ethnic populations, which may partially explain the interethnic variability found in CYP2A6-related metabolic activity (e.g. nicotine metabolism), behaviors (i.e. smoking) and disease (i.e. lung cancer). Investigations of the genetic variation of CYP2A6 and its resulting effects on metabolism and health consequences are still fairly early; this review summarizes what is presently known about CYP2A6, its genetic variants and their clinical consequences.

Aryl Hydrocarbon Hydroxylases↗
PubMed2002

Reduced (+/-)-3,4-methylenedioxymethamphetamine ("Ecstasy") metabolism with cytochrome P450 2D6 inhibitors and pharmacogenetic variants in vitro.

"Ecstasy" [(+/-)-3,4-methylenedioxymethamphetamine or MDMA] is a CNS stimulant, whose use is increasing despite evidence of long-term neurotoxicity. In vitro, the majority of MDMA is demethylenated to (+/-)-3,4-dihydroxymethamphetamine (DHMA) by the polymorphic cytochrome P450 2D6 (CYP2D6). We investigated the demethylenation of MDMA and dextromethorphan (DEX), as a comparison drug, in reconstituted microsomes expressing the variant CYP2D6 alleles (*)2, (*)10, and (*)17, all of which have been linked to decreased enzyme activity. With MDMA, intrinsic clearances (V(max)/K(m)) in CYP2D6.2, CYP2D6.17, and CYP2D6.10 were reduced 15-, 13-, and 135-fold, respectively, compared with wild-type CYP2D6.1. With DEX, intrinsic clearances were reduced by 37-, 51-, and 164-fold, respectively. It was evident that CYP2D6.17 displayed substrate-specific changes in drug affinity (K(m)). Compounds potentially used with MDMA [fluoxetine, paroxetine, (-)-cocaine] demonstrated significant inhibition of MDMA metabolism in both human liver and CYP2D6.1-expressing microsomes. These data demonstrate that individuals possessing the CYP2D6(*)2, (*)17, and, particularly, (*)10 alleles may show significantly reduced MDMA metabolism. These individuals, and those taking CYP2D6 inhibitors, may demonstrate altered acute and/or long-term MDMA-related toxicity.

Alleles↗
PubMed2002

Regional and cellular expression of CYP2D6 in human brain: higher levels in alcoholics.

Cytochrome P450 (CYP) 2D6 is expressed in liver, brain and other extrahepatic tissues where it metabolizes a range of centrally acting drugs and toxins. As ethanol can induce CYP2D in rat brain, we hypothesized that CYP2D6 expression is higher in brains of human alcoholics. We examined regional and cellular expression of CYP2D6 mRNA and protein by RT-PCR, Southern blotting, slot blotting, immunoblotting and immunocytochemistry. A significant correlation was found between mean mRNA and CYP2D6 protein levels across 13 brain regions. Higher expression was detected in 13 brain regions of alcoholics (n = 8) compared to nonalcoholics (n = 5) (anovap < 0.0001). In hippocampus this was localized in CA1-3 pyramidal cells and dentate gyrus granular neurons. In cerebellum this was localized in Purkinje cells and their dendrites. Both of these brain regions, and these same cell-types, are known to be susceptible to alcohol damage. For one case, a poor metabolizer (CYP2D6*4/*4), there was no detectable CYP2D6 protein, confirming the specificity of the antibody used. These data suggest that in alcoholics elevated brain CYP2D6 expression may contribute to altered sensitivity to centrally acting drugs and to the mediation of neurotoxic and behavioral effects of alcohol.

Adult↗
PubMed2002

Factors influencing cotinine half-life during smoking abstinence in African American and Caucasian women.

Cotinine, the proximate metabolite of nicotine, has been identified as an indicator of smoke constituent exposure. Higher cotinine levels in African American cigarette smokers have been identified. Because African Americans experience disproportionate smoking-related morbidity and mortality, it is important to examine potential factors influencing these higher levels of cotinine. The current study examined selected factors of ethnicity, menthol cigarette preference, body composition and alcohol-use history on cotinine half-life in 6 days of smoking abstinence in African American and Caucasian women. A 7-day inpatient protocol was conducted in the General Clinical Research Center, in which day 1 was ad lib smoking and days 2-7 were smoking abstinence (n = 32). Plasma cotinine was measured every 8 h throughout. Average cotinine half-life was 21.3 h, similar to previously reported 18-20 h. Three women exhibited >14 ng/ml cotinine after 136 h of smoking abstinence. Host factors explaining 52.0% of variance in cotinine half-life and associated with longer half-life were being an African American menthol smoker, fewer years of alcohol use and greater lean body mass. Among menthol smokers, baseline cotinine level and cotinine half-life were not significantly different in Caucasian and African American women. Intra-individual cotinine half-life variation and CYP2A6 genotype were examined in substudies. To improve accuracy in correctly classifying non-smokers with cotinine levels, a period of at least 7 days of smoking abstinence may be warranted.

Black or African American↗
PubMed2002

Treatment of codeine dependence with inhibitors of cytochrome P450 2D6.

Codeine is O-demethylated by cytochrome P450 2D6 (CYP2D6) to form the more potent drug morphine, accounting for much of codeine's analgesic and dependence-producing properties. Because morphine production can be decreased by inhibition of CYP2D6, the authors hypothesized that CYP2D6 inhibition could be used to treat codeine dependence. A randomized, double-blind, placebo-controlled trial was conducted. All patients received brief behavioral therapy. Two weeks of baseline monitoring were followed by 8 weeks of daily treatment with fluoxetine or quinidine (two potent CYP2D6 inhibitors) or placebo. Thirty patients were assessed (all white, age 40 + 12 years using 127 + 79 mg/day of codeine [mean + SD]), and 17 entered treatment. Eight patients remained in the study by treatment week 8. Quinidine > fluoxetine > placebo inhibited CYP2D6 as reflected in the change of the O-demethylation of dextromethorphan, a specific CYP2D6 probe. At treatment week 8, placebo, quinidine, and fluoxetine reduced mean daily codeine intake by 57%, 56%, and 51% of baseline intake respectively; there was no difference among treatment groups. In this small sample, CYP2D6 inhibitors did not appear to have a useful role in the treatment of codeine dependence.

Adult↗
PubMed2002

Designer drugs that are potent inhibitors of CYP2D6.

Some abused drugs are substrates of CYP2D6 (e.g., paramethoxyamphetamine, methylenedioxy-methamphetamine). CYP2D6 inhibition by concurrently used drugs of abuse could potentiate such drugs and increase acute toxicity. Ten designer drugs were tested as inhibitors of CYP2D6. Only 1-methyl-4-phenyl-4-propionoxypiperidine (MPPP) and 1-[2-phenylethyl]-4-phenyl-4-acetoxypiperidine (PEPAP) interacted significantly (Ki 1.6 microM and 0.3 microM, respectively). Both are synthetic analogues of meperidine sold as "synthetic heroin." No CYP2D6-mediated metabolites were detected for either compound. Concurrent oral use of CYP2D6 substrates with MPPP and PEPAP may represent a kinetic drug interaction risk, but this risk must be confirmed clinically.

Cytochrome P-450 CYP2D6↗
PubMed2002

Genetic variation in CYP2A6-mediated nicotine metabolism alters smoking behavior.

Approximately 50% of the initiation of tobacco dependence is genetically influenced, whereas maintenance of dependent smoking behavior and amount smoked have approximately 70% genetic contribution (1-5). Determining the variation in nicotine's inactivation is important because of nicotine's role in producing tobacco dependence and regulating smoking patterns (6-11). The genetically polymorphic CYP2A6 enzyme is responsible for the majority of the metabolic inactivation of nicotine to cotinine (12-14). Both in vitro and in vivo studies have demonstrated considerable interindividual variation in CYP2A6 activity (15-17). CYP2A6 is genetically polymorphic, individuals carrying inactive CYP2A6 alleles have decreased nicotine metabolism, are less likely to become smokers and if they do, they smoke fewer cigarettes per day (13,18,19). The decrease in smoking behavior was confirmed by measuring carbon monoxide (CO, a measure of smoke inhalation) levels, plasma and urine nicotine and cotinine levels, and cigarette counts (13,18,19). A duplication variant in the CYP2A6 gene locus has been identified which increases nicotine inactivation and increases smoking (19). CYP2A6 can also activate tobacco smoke procarcinogens (e.g. NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone); current studies are investigating the role of CYP2A6 in risk for lung cancer. Based on these epidemiologic data it was postulated that inhibition of CYP2A6 activity might be useful in a therapeutic context. Kinetic studies in humans indicated that selective CYP2A6 inhibitors decrease the metabolic removal of nicotine. It was also shown that inhibiting CYP2A6 in vivo (phenocopying, or mimicking the genetic defect) in smokers results in decreased smoking, making nicotine orally bioavailable, and the rerouting of procarcinogens to detoxifying pathways (20-22).

Aryl Hydrocarbon Hydroxylases↗
PubMed2002

Inhibition of cytochromes P450 by antifungal imidazole derivatives.

The interactions of a panel of antifungal agents with cytochromes P450 (P450s), as a means of predicting potential drug-drug interactions, have not yet been investigated. The objective of this study was to evaluate the specificity and selectivity of five antifungal agents using selective probe reactions for each of the eight major P450s. The index reactions used were phenacetin O-deethylation (for CYP1A2), coumarin 7-hydroxylation (CYP2A6), diclofenac 4'-hydroxylation (CYP2C9), omeprazole 5-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), 7-ethoxy-4-trifluoromethylcoumarin deethylation (CYP2B6), chlorzoxazone 6-hydroxylation (CYP2E1), and omeprazole sulfonation (CYP3A4). Five antifungal agents that include an imidazole moiety (clotrimazole, miconazole, sulconazole, tioconazole, and ketoconazole) were examined in cDNA-expressing microsomes from human lymphoblast cells or human liver microsomes. All inhibitors studied demonstrated nonselective inhibition of P450s. Ketoconazole seemed to be the most selective for CYP3A4, although it also inhibited CYP2C9. High-affinity inhibition was seen for CYP1A2 (sulconazole and tioconazole K(i), 0.4 microM), CYP2B6 (miconazole K(i), 0.05 microM; sulconazole K(i), 0.04 microM), CYP2C19 (miconazole K(i), 0.05 microM; sulconazole K(i), 0.008 microM; tioconazole K(i), 0.04 microM), CYP2C9 (sulconazole K(i), 0.01 microM), CYP2D6 (miconazole K(i), 0.70 microM; sulconazole K(i), 0.40 microM), CYP2E1 (tioconazole K(i), 0.4 microM), and CYP3A4 (clotrimazole K(i), 0.02 microM; miconazole K(i), 0.03 microM; tioconazole K(i), 0.02 microM). Therefore, this class of compounds is likely to result in significant drug-drug interactions in vivo.

Animals↗
PubMed2002

Metabolism of 18-methoxycoronaridine, an ibogaine analog, to 18-hydroxycoronaridine by genetically variable CYP2C19.

18-Methoxycoronaridine, a newly developed ibogaine analog, has been reported to decrease the self-administration of morphine, cocaine, ethanol, and nicotine. It has also been reported to attenuate naltrexone-precipitated signs of morphine withdrawal. In this study, three metabolites of 18-methoxycoronaridine (18-MC) were separated and identified by high-performance liquid chromatography-electrospray ionization-mass spectrometry-mass spectrometry (HPLC-ESI-MS-MS); the major metabolite was 18-hydroxycoronaridine (18-HC). The other two metabolites were elucidated as hydroxylated metabolites on the basis of their MS-MS spectra. Catalytic studies of 18-MC O-demethylase activity in human liver microsomes indicate that one high affinity enzyme is involved in this reaction (K(m) from 2.81 to 7.9 microM; V(max) from 0.045 to 0.29 nmol/mg/min). In cDNA-expressing microsomes, only CYP2C19 displayed significant 18-MC O-demethylase activity (K(m) 1.34 microM; V(max) 0.21 nmol/mg/min). S-Mephenytoin, a selective CYP2C19 inhibitor, inhibited 18-MC O-demethylation by 65% at a concentration of 2 times its K(I), and antibodies against rat 2C (human CYP2C8, 2C9, 2C19) inhibited 18-HC formation by 70%. Studies with other cytochrome P450 (P450)-selective chemical inhibitors and antibodies failed to demonstrate an appreciable role for other P450s in this reaction. In addition, in microsomes from five different human livers, 18-MC O-demethylation correlated with S-mephenytoin 4'hydroxylase activity but not with other P450 probe reactions. These data indicate that 18-HC formation is the predominant pathway of 18-MC metabolism in vitro in human liver microsomes and that this metabolic pathway is primarily catalyzed by the polymorphic CYP2C19. The apparent selectivity of this pathway for CYP2C19 suggests 18-MC as a potentially useful probe of CYP2C19 activity in vitro and in vivo.

Animals↗
PubMed2002

The role of pharmacogenetically-variable cytochrome P450 enzymes in drug abuse and dependence.

The risk of drug dependence is determined by the interaction of drug, individual and environment. 'Pharmacogenetics' is the study of the influence of heredity on the response to drugs and their fate in the body; these studies aim to improve the understanding of inter-individual variability in drug response. The authors have applied this research approach to the study of drug metabolism and dependence. Specifically the interaction of genetically variable hepatic cytochrome P450 (CYP) enzymes and their effect on self-administration of drugs has been examined. Many drugs of abuse are substrates (e.g., amphetamines, codeine, nicotine) or inhibitors (e.g., (-)-cocaine) of polymorphic CYPs. Drug metabolism by genetically polymorphic enzymes can have significant clinical implications relating to drug toxicity, therapeutic failure, drug-drug interactions, disease susceptibility and abuse liability. There is good evidence that drug metabolism by genetically variable CYPs can influence the risk of drug dependence, the amount of drug consumed by dependent individuals and some of the toxicities associated with drug-taking behavior. It is anticipated that pharmacogenetics will be used to identify individuals at a greater risk for specific drug dependencies, provide information that can lead to novel treatment and prevention approaches as well as provide guidance for individualization of treatment choice.

Animals↗