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Biomedical subjects

R F Tyndale

Publications and source records attributed to R F Tyndale.

At least 37 records · Page 2Linked to original sources
PubMed2000

Regional and cellular induction of nicotine-metabolizing CYP2B1 in rat brain by chronic nicotine treatment.

In the rat, nicotine is metabolized to cotinine primarily by hepatic cytochrome P450 (CYP) 2B1. This enzyme is also found in other organs such as the lung and the brain. Hepatic nicotine metabolism is unaltered after nicotine exposure; however, nicotine may regulate CYP2B1 in other tissues. We hypothesized that nicotine induces its own metabolism in brain by increasing CYP2B1. Male rats were treated with nicotine (0.0, 0.1, 0.3, or 1.0 mg base/kg in saline) s.c. daily for 7 days. CYP2B1 mRNA and protein were assayed in the brain and liver by reverse transcriptase-polymerase chain reaction (RT-PCR), immunoblotting, and immunocytochemistry. In control rats, CYP2B1 mRNA and protein expression were brain region- and cell-specific. CYP2B1 was not induced in the liver, but CYP2B1 mRNA and protein showed dose-dependent, region- and cell-specific patterns of induction across brain regions. At 1.0 mg nicotine/kg, the largest increase in protein was in the brain stem (5.8-fold, P < 0.05) with a corresponding increase in CYP2B1 mRNA (7.6-fold, P < 0.05). Induction of CYP2B1 was also observed in the frontal cortex, striatum, and olfactory tubercle. Immunocytochemistry showed that induction was restricted principally to neurons. These data indicate that nicotine may alter its own metabolism in the brain through transcriptional regulation, perhaps contributing to central tolerance to the effects of nicotine. CYP2B1 and its human homologue CYP2B6 also activate tobacco smoke procarcinogens such as NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]. Highly localized increases in CYP2B could result in increased mutagenesis. These data suggest roles for nicotine-induced CYP2B in central metabolic tolerance, nicotine-induced neurotoxicity, neuroplasticity, and carcinogenesis.

Animals↗
PubMed2000

The influence of an endogenous beta3 subunit on recombinant GABA(A) receptor assembly and pharmacology in WSS-1 cells and transiently transfected HEK293 cells.

Cell lines are commonly used for studying recombinant heterooligomeric ion channels with defined subunit composition. Such studies often ignore the contribution of endogenous proteins in the assembly of mature channels. We examined whether an endogenous subunit was required for the functional expression of gamma-aminobutyric acid type A (GABA(A)) receptors in WSS-1 cells, HEK293 cells stably expressing recombinant alpha1 and gamma2 subunits. Our pharmacological and RT-PCR analyses of GABA(A) receptors and their mRNAs in WSS-1 cells confirm the presence of alpha1 and gamma2 subunits and suggest the existence of an endogenous beta3 subunit. Whole-cell GABA-evoked currents recorded from untransfected WSS-1 cells were blocked by bicuculline methiodide and enhanced by anesthetics and anticonvulsants including the subunit-selective compounds diazepam and loreclezole. These data suggest that, in addition to the gamma2 subunit, WSS-1 cell receptors also contain beta2/3 subunits. RT-PCR revealed that WSS-1 cells and parental HEK293 cells contain beta3 mRNA. We examined the contribution of the beta3 subunit in the function of receptors formed by expression of alpha1 and gamma2S subunits. Untransfected HEK293 cells were unresponsive to GABA. Cells transfected with alpha1 and gamma2S cDNAs displayed small diazepam and loreclezole responsive GABA-activated currents. By contrast, the expression of alpha1 and gamma2S cDNAs in the neuroblastoma NB41A3 cell line, that lacks beta subunit mRNAs, failed to produce functional receptors. These data reaffirm that alpha1 and gamma2S subunits alone do not form functional GABA(A) receptors and that receptors of WSS-1 cells contain alpha1, beta3 and gamma2S subunits.

Animals↗
PubMed2000

Human dopamine transporter gene: coding region conservation among normal, Tourette's disorder, alcohol dependence and attention-deficit hyperactivity disorder populations.

The dopamine transporter (DAT) provides major regulation of the synaptic levels of dopamine and is a principal target of psychostimulant drugs. Associations between DAT gene polymorphisms and human disorders with possible links to dopaminergic neurotransmission, including attention-deficit/hyperactivity disorder (ADHD) and consequences of cocaine and alcohol administration, have been reported. We now report approximately 60000 bp of genomic sequence containing the entire DAT gene. This sequence was used to amplify each of the 15 DAT gene exons and several introns and analyze these amplification products by single-stranded sequence conformation (SSCP) and/or direct sequencing. These results define silent allelic single nucleotide sequence variants in DAT gene exons 2, 6, 9 and 15. Rare conservative mutations are identified in amino acids encoded by DAT exons 2 and 8. Analyses of the common nucleotide variants and the previously reported VNTR in the non-coding region of exon 15 define the pattern of linkage disequilibrium across the DAT locus. These comprehensive analyses, however, fail to identify any common protein coding DAT sequence variant in more than 150 unrelated individuals free of neuropsychiatric disease, 109 individuals meeting City of Hope criteria for Tourette's syndrome, 64 individuals with DSM-IV diagnoses of ethanol dependence, or 15 individuals with ADHD. These data are consistent with substantial evolutionary conservation of the DAT protein sequence. They suggest that gene variants that alter levels of DAT expression provide the best current candidate mechanism for reported associations between DAT gene markers, ADHD and other more tentatively associated neuropsychiatric disorders.

Adolescent↗
PubMed2000

Inhibition of cytochrome P450 2A6 increases nicotine's oral bioavailability and decreases smoking.

BACKGROUND: Nicotine establishes and maintains tobacco dependence. Individuals with genetically deficient CYP2A6 nicotine metabolism are at lower risk to become smokers and, if dependent, will smoke fewer cigarettes. Hepatic CYP2A6 accounts for nicotine's low systemic bioavailability, precluding oral nicotine replacement to treat dependence. OBJECTIVE: We sought to determine whether CYP2A6 inhibition via oral methoxsalen decreases nicotine clearance, increases nicotine bioavailability, and decreases smoking. METHODS: Two within-subject designs in healthy tobacco-dependent volunteers were conducted: a singleblind kinetic study (n = 17) of methoxsalen 30, 10, or 3.5 mg or placebo given with nicotine 4 mg orally to abstinent smokers; and a double-blind randomized crossover study (n = 11) of methoxsalen 30 mg or placebo crossed with nicotine 4 mg given orally or placebo before 60 minutes' abstinence and 90 minutes' free smoking. RESULTS: Placebo plus nicotine 4 mg orally increased the mean 3-hour plasma nicotine level by 4 ng/mL over residual baseline nicotine level, whereas methoxsalen 10 or 30 mg plus nicotine increased it by 9 ng/mL (P<.01), demonstrating in vivo inhibition of CYP2A6 nicotine metabolism. Methoxsalen 30 mg plus nicotine 4 mg given orally decreased breath carbon monoxide concentration at the end of free smoking by 47% (4.6 versus 8.7 ppm; P<.01) and cigarettes smoked by 24% (3.1 versus 4.1, P<.01) compared with placebo plus placebo. CONCLUSIONS: Methoxsalen inhibits nicotine first-pass metabolism of orally administered nicotine, and the combination directly reduces smoking in a laboratory setting. CYP2A6 inhibitors may have an important role in smoking cessation and tobacco exposure reduction.

Administration, Oral↗
PubMed2000

Regional and cellular distribution of CYP2D subfamily members in rat brain.

1. Human CYP2D6 is present in brain, metabolizes many drugs and has been implicated in Parkinson's and Alzheimer's diseases and some cancers. It is still unclear which of the six known rat CYP2D subfamily members is/are homologous to human CYP2D6. 2. In this study, RT-PCR, Southern and Western blotting and immunohistochemical techniques were used to study the distribution of CYP2D subfamily member mRNA and proteins across 10 rat brain regions. CYP2D subfamily mRNA and protein levels were correlated with brain dextromethorphan O-demethylation (DOD), a measure of human CYP2D6 and rat CYP2D1 activities. 3. The data showed a strong relationship between CYP2D1 and CYP2D1-18 with brain DOD activity. In addition, it was shown that CYP2D proteins are present in brain mitochondrial as well as microsomal membranes. CYP2D subfamily member mRNA and proteins varied across brain regions and were highly concentrated in specific cell types. 4. These data strongly suggest that CYP2D1 and not CYP2D5 mediates DOD activity in rat brain, and may be the rat homologue of human CYP2D6. The highly localized nature of CYP2D indicates that in specific neurones enzyme levels may approach hepatic levels and, hence, contribute to local alterations in brain drug metabolism.

Alcohol Oxidoreductases↗
PubMed2000

Cytochrome P450 2D6 and treatment of codeine dependence.

Oral opioid analgesics such as codeine are used extensively worldwide and are frequently misused. Codeine is a substrate of CYP2D6, a genetically polymorphic P450 enzyme, and is metabolized to the more potent drug morphine. CYP2D6 activity can be inhibited by fluoxetine, and the inhibition of morphine formation may help individuals reduce their use of codeine. Fourteen long-term users of oral opiates (principally codeine) were assessed for an open-label pilot treatment study of fluoxetine 20 mg/day combined with a brief behavioral intervention and structured tapering of the opiate. Eight subjects entered and completed the 8-week treatment. Opiate use decreased by 30% to 100% of baseline use (p < 0.0001) in parallel with a decrease in CYP2D6 activity. Fluoxetine may have a role in the treatment of opiate dependence by decreasing opiate-reinforcing properties.

Adult↗
PubMed2000

Inhibition of cytochrome P450 2D6 modifies codeine abuse liability.

Oral codeine preparations, widely used for analgesia and cough suppression, are abused by some individuals for their mood-altering properties. The enzymatic O-demethylation of codeine is catalyzed by cytochrome P450 2D6 (CYP2D6), leading to the production of metabolites (morphine, morphine-6-glucuronide) that are pharmacologically more potent than codeine. A placebo-controlled, single-blind study was conducted to characterize the subjective effects of codeine associated with abuse liability and to determine the importance of metabolic O-demethylation to codeine abuse liability. Twelve non-drug-dependent subjects received oral administration of placebo and codeine 60, 120, and 180 mg, and a favorite dose (FD) was determined for each subject. The FD was readministered after pretreatment with placebo, 50 mg of quinidine (a specific, selective CYP2D6 inhibitor) once, or 50 mg of quinidine given four times a day for 4 days. Single-dose quinidine pretreatment significantly decreased the recovery of O-demethylated metabolites in plasma (p < 0.01) and resulted in a decrease in the positive (e.g., "high," p < 0.05) and negative (e.g., nausea, p < 0.05) subjective effects of codeine in both the FD120 and FD180 groups. Short-term quinidine pretreatment inhibited codeine O-demethylation more than did single-dose quinidine pretreatment (p < 0.01), and it decreased positive codeine effects in the FD120 group (N = 7), but unexpectedly not in the FD180 group (N = 5). These results suggest that the O-demethylated metabolites contribute substantially to the subjective effects and abuse liability of codeine.

Adult↗
PubMed2000

Ibogaine: complex pharmacokinetics, concerns for safety, and preliminary efficacy measures.

Ibogaine is an indole alkaloid found in the roots of Tabernanthe Iboga (Apocynaceae family), a rain forest shrub that is native to western Africa. Ibogaine is used by indigenous peoples in low doses to combat fatigue, hunger and thirst, and in higher doses as a sacrament in religious rituals. Members of American and European addict self-help groups have claimed that ibogaine promotes long-term drug abstinence from addictive substances, including psychostimulants and opiates. Anecdotal reports attest that a single dose of ibogaine eliminates opiate withdrawal symptoms and reduces drug craving for extended periods of time. The purported efficacy of ibogaine for the treatment of drug dependence may be due in part to an active metabolite. The majority of ibogaine biotransformation proceeds via CYP2D6, including the O-demethylation of ibogaine to 12-hydroxyibogamine (noribogaine). Blood concentration-time effect profiles of ibogaine and noribogaine obtained for individual subjects after single oral dose administrations demonstrate complex pharmacokinetic profiles. Ibogaine has shown preliminary efficacy for opiate detoxification and for short-term stabilization of drug-dependent persons as they prepare to enter substance abuse treatment. We report here that ibogaine significantly decreased craving for cocaine and heroin during inpatient detoxification. Self-reports of depressive symptoms were also significantly lower after ibogaine treatment and at 30 days after program discharge. Because ibogaine is cleared rapidly from the blood, the beneficial aftereffects of the drug on craving and depressed mood may be related to the effects of noribogaine on the central nervous system.

Adult↗
PubMed2000

Mimicking gene defects to treat drug dependence.

The genetic basis for drug dependence has focused on genes that encode receptors involved in the reinforcing properties of drugs of abuse or that determine drug-taking behavior (e.g. impulsivity, etc.). Pharmacogenetic variations in the patterns of metabolism among individuals can also importantly modulate the risk of drug dependence. Cytochrome P450 drug metabolizing enzymes (CYPs), can activate (e.g. codeine to morphine) or deactivate (e.g. nicotine to cotinine) drugs of abuse. Some CYPs are polymorphic, that is, there are gene mutations which result in individuals with no (null mutations) or decreased enzyme activity (e.g. CYP2D6*10). Individuals with two null mutations appear in the population as phenotypic poor metabolizers. Using in vitro studies, we have identified drugs of abuse that are substrates of the polymorphic enzymes CYP2D6 (codeine, amphetamines, dextromethorphan), CYP2A6 (nicotine) and CYP2C19 (flunitrazepam). In human experimental studies, we have shown that CYP phenotype and genotype affect abuse liability of CYP2D6 metabolized drugs of abuse. In addition, we inhibited CYP2D6 and decreased individuals' risk of dependence experimentally (codeine, dextromethorphan) and treated codeine dependence. In epidemiologic studies CYP2D6 and CYP2A6 null mutations protect individuals from becoming codeine and tobacco dependent, respectively. With respect to CYP2A6, individuals with mutations, smoke fewer cigarettes and can quit more easily. Inhibiting CYP2A6 (e.g. tranylcypromine, methoxsalen) decreases smoking and the activation of procarcinogens. By mimicking these gene defects the risk of dependence can be decreased in individuals and new treatments developed.

Animals↗
PubMed2000

Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking.

In humans, 80% of nicotine is metabolized to the inactive metabolite cotinine by the enzyme CYP2A6, which can also activate tobacco smoke procarcinogens (e.g., 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone). Previously, we demonstrated that individuals who are nicotine-dependent and have defective CYP2A6 alleles (*2, *3) smoked fewer cigarettes; however, we recognize that the genotyping method used for the CYP2A6*3 allele gave a high false-positive rate. In the current study we used improved genotyping methods to examine the effects of the defective CYP2A6*2 and CYP2A6*4 alleles on smoking behavior. We found that those with the defective alleles (N = 14) smoked fewer cigarettes per day than those homozygous (N = 277) for wild-type alleles (19 versus 28 cigarettes per day, P <.001). In addition, we identified a duplicated form of the CYP2A6 gene, corresponding to the gene deletion CYP2A6*4 allele, developed a genotyping assay, assessed the gene copy number, and examined its prevalence in Caucasian smokers (N = 296). We observed an ascending rank order for plasma cotinine and breath carbon monoxide levels (an index of smoke inhalation) in individuals with null (CYP2A6*2 and CYP2A6*4) alleles (N = 14), those homozygous for wild-type (CYP2A6*1/*1) alleles (N = 277), and those with our newly identified CYP2A6 gene duplication (N = 5). The phenotype, as determined by plasma nicotine/cotinine ratios, had a descending rank order for these three genotype groups that did not reach significance. Although further characterization is required for the duplication gene variant, these results extend our previous findings and suggest a substantial influence of CYP2A6 genotype and phenotype on smoking behavior.

Adolescent↗
PubMed1999

A common genetic defect in nicotine metabolism decreases risk for dependence and lowers cigarette consumption.

Nicotine is the primary compound present in tobacco that is responsible for establishing and maintaining tobacco dependence; dependent smokers adjust their smoking behavior to maintain peripheral and central nicotine levels. CYP2A6 is the enzyme responsible for the majority of the inactivation of nicotine in humans. This enzyme is also responsible for activating tobacco-related procarcinogens such as the nitrosamines. This paper outlines how genetic variation in the CYP2A6 gene may protect individuals from becoming nicotine-dependent smokers, and if dependent, how impairment of the CYP2A6 gene function decreases the number of cigarettes consumed by smokers (Pianezza M, Sellers EM, Tyndale RF. 1998. A common genetic defect in nicotine metabolism decreases smoking. Nature 393(6687):750). We also discuss recent findings which suggest that mimicking this gene defect by inhibiting CYP2A6 decreases nicotine metabolism and smoking. Further research is needed in order to improve our understanding of how genetic variation in CYP2A6 alters the risk for nicotine dependence and lowers nicotine consumption. This includes a better understanding of how the genetic variants alter nicotine metabolism in vivo in males and females as well as the role of CYP2A6 genetic variation in risk for tobacco-related cancers. In addition we need to gain a better understanding of how manipulating this enzyme could be used therapeutically in prevention and treatment of smoking as well as in exposure reduction.

Alleles↗
PubMed1999

Characterization of cytochrome P-450 2D1 activity in rat brain: high-affinity kinetics for dextromethorphan.

We investigated the enzymatic function, stability, and regional distribution of rat brain cytochrome P-450 (CYP) 2D1 activity. CYP2D1 is the homolog of human CYP2D6, a genetically variable enzyme that activates or inactivates many clinical drugs acting on the central nervous system (e.g., antidepressants, monoamine oxidase inhibitors, serotonin uptake inhibitors, and neuroleptics), drugs of abuse (e.g., amphetamine and codeine), neurotoxins (e.g., 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1,2,3, 4-tetrahydroquinoline), and endogenous neurochemicals (e.g., tryptamine). The CYP2D family has been identified in rodent, canine, and primate brain. Conversion of dextromethorphan to dextrorphan by rat brain membranes was assayed by HPLC and was dependent on NADPH, protein concentration, and incubation time. Significant loss of activity was observed in some homogenizing buffers and after freezing of whole tissues or membrane preparations. Dextromethorphan (0.5-640 microM) metabolism was mediated by high- and low-affinity enzyme systems; K(m1) was 2.7 +/- 2.6 and K(m2) was 757 +/- 156 microM (n = 3 rats, mean +/- S.E.). The enzyme activity was significantly (p <.01) and stereoselectively inhibited by CYP2D1 inhibitors quinine and quinidine (not by CYP2C or CYP3A inhibitors), and by anti-CYP2D6 peptide antiserum (not by anti-CYP2C, -CYP2B, or -CYP3A antibodies). The enzymatic activity demonstrated significant brain regional variation (n = 10 regions, p <.001). These data characterize CYP2D1-mediated dextromethorphan metabolism in rat brain and suggest that localized metabolism of other CYP2D1 substrates (drugs, neurotoxins, and possibly endogenous compounds) within the brain will occur. In humans, CYP2D6 is genetically polymorphic; the variable expression of brain CYP2D6 may result in interindividual differences in central drug and neurotoxin metabolism, possibly contributing to interindividual differences in drug effects and neurotoxicity.

Alcohol Oxidoreductases↗
PubMed1998

Canadian Native Indians exhibit unique CYP2A6 and CYP2C19 mutant allele frequencies.

Many human cytochromes P450 (CYP) enzymes are polymorphically expressed, resulting in interindividual and interethnic differences in the metabolism of substrate drugs. Little is known about the genetic variation of CYP enzymes in Canadian Native Indians. We therefore determined the CYP2C19 and CYP2A6 mutant allele frequencies in 159 Canadian Native Indians and compared them with white and Asian subjects. Canadian Native Indians differed significantly from both white and Asian populations in allelic patterns of both CYP2C19 (19.1% CYP2C19*2 and 0% CYP2C19*3) and CYP2A6 (0.9% CYP2A6*2 and 13.9% CYP2A6*3). In addition, analysis of the Canadian Native Indian data suggested that there may be an association between the presence of the CYP2C19 and CYP2A6 mutant alleles such that the co-occurrence of these 2 alleles is higher than would be predicted on the basis of their individual frequencies in this population.

Alleles↗
PubMed1998

A conditionally immortalized glial cell line that expresses mature myelin proteins and functional GABA(A) receptors.

We have isolated and characterized a conditionally immortalized glial cell line that expresses mature myelin proteins, as well as functional GABA(A) receptors. Glial cells were isolated from postnatal day 1 H-2Kb-tsA58 transgenic mice that contain the temperature-sensitive SV40 large T antigen oncogene under the control of an interferon-gamma-inducible promoter. A clonal line was isolated that grew rapidly under permissive conditions (33 degrees C in the presence of interferon-gamma), but not under nonpermissive conditions (37 degrees C in the absence of interferon-gamma). Cells expressed mRNAs of mature myelin proteins (myelin basic proteins and proteolipid protein) when grown under either permissive or nonpermissive conditions, but myelin basic proteins were detected only when cells were maintained at 37 degrees C. GABA induced an increase in intracellular calcium concentration, indicating the presence of functional receptors for this transmitter. Characterization of the GABA-evoked calcium response and whole-cell currents indicated that these responses were mediated by GABA(A) receptors. Reverse transcription-polymerase chain reaction revealed differential expression of mRNAs for specific GABA(A) receptor subunits. Messages for the alpha2, alpha4, beta1, and delta subunits were readily detected by reverse transcription-polymerase chain reaction, whereas messages for the alpha1, alpha3, alpha5, alpha6, beta2, beta3, and gamma1-3 subunits were not. As this cell line can be easily propagated and differentiated, it should provide a valuable tool in studying not only the development of oligodendroglia, but also the function of their transmitter receptors and myelin proteins.

Animals↗
PubMed1998

Psychotropic effects of dextromethorphan are altered by the CYP2D6 polymorphism: a pilot study.

Dextromethorphan is a nonopioid antitussive metabolized by cytochrome P450 2D6 (CYP2D6) to an active metabolite, dextrorphan. CYP2D6 is polymorphically expressed in humans, with 5 to 10% of Caucasians being homozygous deficient for the active form of the enzyme. In a pilot study, the authors investigated the pharmacologic effects of dextromethorphan in individuals phenotyped and genotyped as extensive metabolizers (EMs, N = 4) and poor metabolizers (PMs, N = 2) of CYP2D6 substrates. Dextromethorphan doses ranged from 0 to 6 mg/kg based on individual subject tolerance. All EMs tolerated 3 to 6 mg/kg dextromethorphan, whereas PMs barely tolerated 3 mg/kg dextromethorphan and therefore received lower doses. As shown in previous studies, plasma kinetics show profound differences in dextromethorphan metabolism between EMs and PMs. Dextromethorphan produced qualitatively and quantitatively different objective and subjective effects in the two groups. Objectively, PMs had greater psychomotor impairment, as measured by a joystick tracking task, compared with EMs on 3 mg/kg dextromethorphan (mean performance +/- SE, 95+/-0.5% for EMs vs. 86+/-6% for PMs; p < 0.05). At this dose, EMs also reported greater abuse potential compared with PMs (p < 0.05), and PMs reported greater sedation and dysphoria compared with EMs (p < 0.01). These data provide preliminary evidence that dextrorphan contributes to dextromethorphan abuse liability, and therefore PMs may be less likely to abuse dextromethorphan.

Adult↗
PubMed1998

NAD(P)H:quinone oxidoreductase: polymorphisms and allele frequencies in Caucasian, Chinese and Canadian Native Indian and Inuit populations.

NAD(P)H:quinone oxidoreductase (NQO1) catalyses the two-electron reduction of quinone compounds. NQO1 is involved in the reductive bioactivation of cytotoxic antitumour quinones such as mitomycin C, but also plays a protective role against the carcinogenicity and mutagenicity of quinones, their precursors and metabolites. Three alleles have been identified in the human population: the functional Arg139/Pro187 allele (which we have termed NQO1*1); the nonfunctional allele Arg139/Ser187 (NQO1*2) and the Trp139/Pro187 allele (NQO1*3), which is associated with a diminished activity. We applied polymerase chain reaction-based genotyping assays to characterize interethnic variability in the frequency of NQO1 alleles in Caucasian (n = 575), Canadian Native Indian (n = 110), Canadian Inuit (n = 83) and Chinese (n = 86) populations. The NQO1*2 allele was found at significantly higher frequencies in Chinese (0.49) and Native North American populations (Inuit 0.46; Canadian Native Indians 0.40) compared with Caucasians (0.16). The NQO1*3 allele was not observed in Inuit individuals, and occurred at a lower frequency than the NQO*2 allele in Caucasians (0.05), Chinese (0.04) and Canadian Native Indians (0.01). Our results predict that a greater proportion of Orientals and related ethnic groups lack, or have reduced, NQO activity relative to Caucasians. Affected individuals may not only exhibit resistance to quinone-based cancer therapy because of a decreased production of cytotoxic drug metabolites, but may also be more susceptible to toxicities associated with toxicants.

Alleles↗