Biomedical subjects

A Gaedigk

Publications and source records attributed to A Gaedigk.

At least 19 recordsLinked to original sources

PubMed2000

Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase with the "Cooperstown cocktail".

BACKGROUND: Simultaneous administration of several probes enhances the utility of phenotyping, but poor specificity, side effects, and use of drugs not approved by the Food and Drug Administration limit the usefulness of prior phenotyping cocktails. OBJECTIVES: To evaluate potential drug-drug interactions associated with use of a cocktail of caffeine, omeprazole, dextromethorphan, and midazolam for simultaneous phenotyping of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase. METHODS: Twelve subjects received caffeine + dextromethorphan, omeprazole, and midazolam (each alone), and a cocktail of caffeine + dextromethorphan + omeprazole + midazolam. Blood samples were collected at 120 minutes for omeprazole and 5/-hydroxyomeprazole, and at 0, 5, 30, 60, 120, 240, 300, and 360 minutes for midazolam. Twelve-hour urine samples were collected for analysis of dextromethorphan, caffeine, and metabolites. RESULTS: The median CYP1A2 metabolic ratio after administration of caffeine + dextromethorphan was not significantly different from that obtained with the cocktail (P = .84). Likewise, the median N-acetyltransferase-2, xanthine oxidase, and CYP2D6 metabolic ratios were not significantly different after cocktail administration (P = .977 for each N-acetyltransferase-2; P = .795 for xanthine oxidase; P = .75 for CYP2D6). The median CYP2C19 metabolic ratio after cocktail administration was not significantly different from that obtained after omeprazole administered alone (P = 1.000). Also, midazolam plasma clearance was not significantly different after cocktail administration compared with that after administration of midazolam alone (P = .708). The only side effect was sedation, which was associated with intravenous midazolam and occurred to a similar extent after both individual and cocktail phenotyping. CONCLUSIONS: These results indicate no pharmacokinetic or pharmacodynamic interactions that would limit the utility of this phenotyping cocktail for simultaneous measurement of the activity of multiple drug-metabolizing enzymes.

Administration, Oral↗

PubMed2000

Localization of N-acetyltransferases NAT1 and NAT2 in human tissues.

Human acetyl coenzyme A-dependent N-acetyltransferase (EC 2.3.1.5) (NAT) catalyzes the biotransformation of a number of arylamine and hydrazine compounds. NAT isozymes are encoded at 2 loci; one encodes NAT1, formerly known as the monomorphic form of the enzyme, while the other encodes the polymorphic NAT2, which is responsible for individual differences in the ability to acetylate certain compounds. Human epidemiological studies have suggested an association between the "acetylator phenotype" and particular cancers such as those of the bladder and colon. In the present study, NAT1- and NAT2-specific riboprobes were used in hybridization histochemistry studies to localize NAT1 and NAT2 mRNA sequences in formalin-fixed, paraffin-embedded human tissue sections. Expression of both NAT1 and NAT2 mRNA was observed in liver, gastrointestinal tract tissues (esophagus, stomach, small intestine, and colon), ureter, bladder, and lung. In extrahepatic tissues, NAT1 and NAT2 mRNA expression was localized to intestinal epithelial cells, urothelial cells, and the epithelial cells of the respiratory bronchioles. The observed heterogeneity of NAT1 and NAT2 mRNA expression between human tissue types may be of significance in assessing their contribution to known organ-specific toxicities of various arylamine drugs and carcinogens.

Arylamine N-Acetyltransferase↗

PubMed2000

Interethnic differences of drug-metabolizing enzymes.

Polymorphisms exhibited by drug-metabolizing enzymes are well known and have been investigated for many years. Recently, the exploding field of pharmacogenetics has focused not only on the characterization of enzymes responsible for drug biotransformation but also, on describing the sources of variability in enzyme activity. While initial observations and studies focused on populations of Caucasian origin, reports for other populations followed. The incidence of a poor or slow metabolizer phenotype for a given enzyme caused by allelic variants may vary significantly between populations. The question arises as to whether a prediction of the phenotype (i.e. distribution and/or enzyme activity) can be accurately ascertained from genotype information gathered in a related population. This is exemplified by NAD(P):quinone oxidoreductase (NQO1) investigated in Canadian Native Indian (CNI), Inuit and Chinese populations and the cytochromes P4502C19 and 2D6. While the two North American Native populations are genetically distinct, they are both descendants from northern Asia. Consequently, one might suspect that on a pharmacogenetic basis, CNI and Inuit would be more comparable to Chinese as opposed to Caucasian populations. This is certainly not the case as demonstrated for all three enzymes. Also, for a reliable phenotype prediction, one needs to pay attention to ethnic "mixing" which occurs between certain populations. Ethnic diversity constitutes both a challenge and an opportunity to prudently apply pharmacogenetics so that variability in both drug disposition and effect may be better understood.

Aryl Hydrocarbon Hydroxylases↗

PubMed1999

Crystal structure of human catecholamine sulfotransferase.

Sulfonation, like phosphorylation, can modify the activity of a variety of biological molecules. The sulfotransferase enzymes sulfonate neurotransmitters, drugs, steroid hormones, dietary carcinogens and proteins. SULT1A3 specifically sulfonates catecholamines such as dopamine, adrenaline and noradrenaline. The crystal structure of SULT1A3 with a sulfate bound at the active site, has been determined at 2.4 A resolution. Although the core alpha/beta fold is like that of estrogen and heparan sulfotransferases, major differences occur in and around the active site. Most notably, several regions surrounding the active site, including a section of 40 residues, are disordered in SULT1A3. Regions that are topologically equivalent to the disordered parts of SULT1A3 are involved in substrate and cofactor binding in estrogen and heparan sulfotransferase. Flexibility in these regions suggests that ligand binding elicits a disorder-order transition in and around the active site of sulfotransferases and might contribute to the broad substrate specificity of these enzymes.

Amino Acid Sequence↗

PubMed1999

Structural characterization of human aryl sulphotransferases.

Human aryl sulphotransferase (HAST) 1, HAST3, HAST4 and HAST4v share greater than 90% sequence identity, but vary markedly in their ability to catalyse the sulphonation of dopamine and p-nitrophenol. In order to investigate the amino acid(s) involved in determining differing substrate specificities of HASTs, a range of chimaeric HAST proteins were constructed. Analysis of chimaeric substrate specificities showed that enzyme affinities are mainly determined within the N-terminal end of each HAST protein, which includes two regions of high sequence divergence, termed Regions A (amino acids 44-107) and B (amino acids 132-164). To investigate the substrate-binding sites of HASTs further, site-directed mutagenesis was performed on HAST1 to change 13 individual residues within these two regions to the HAST3 equivalent. A single amino acid change in HAST1 (A146E) was able to change the specificity for p-nitrophenol to that of HAST3. The substrate specificity of HAST1 towards dopamine could not be converted into that of HAST3 with a single amino acid change. However, compared with wild-type HAST1, a number of the mutations resulted in interference with substrate binding, as shown by elevated Ki values towards the co-substrate 3'-phosphoadenosine 5'-phosphosulphate, and in some cases loss of activity towards dopamine. These findings suggest that a co-ordinated change of multiple amino acids in HAST proteins is needed to alter the substrate specificities of these enzymes towards dopamine, whereas a single amino acid at position 146 determines p-nitrophenol affinity. A HAST1 mutant was constructed to express a protein with four amino acids deleted (P87-P90). These amino acids were hypothesized to correspond to a loop region in close proximity to the substrate-binding pocket. Interestingly, the protein showed substrate specificities more similar to wild-type HAST3 than HAST1 and indicates an important role of these amino acids in substrate binding.

Amino Acid Sequence↗

PubMed1999

Dose dependency of dextromethorphan for cytochrome P450 2D6 (CYP2D6) phenotyping.

Most dextromethorphan CYP2D6 phenotyping studies use a 30-mg dose, but data that show superiority of any particular dose are lacking. We compared metabolic ratios from six different dextromethorphan phenotyping doses to ascertain whether linearity existed over a dosage range. Forty subjects were enrolled in the study. Each subject received 0.05 mg/kg, 0.15 mg/kg, 0.3 mg/kg, 30 mg, 0.8 mg/kg, and 1.2 mg/kg dextromethorphan in a randomized crossover fashion. Urinary dextromethorphan to dextrorphan molar ratios were used to measure CYP2D6 activity. Single blood samples were obtained for CYP2D6 genotyping, which revealed one poor metabolizer and 39 extensive metabolizers. A statistical difference was found for the molar ratio between the 0.8 mg/kg and the 1.2 mg/kg dose compared with the other four doses. None of the 39 genotypic extensive metabolizers were incorrectly phenotyped with any of these doses. These data support the use of moderate doses of dextromethorphan for phenotyping to avoid dose dependency.

Adult↗

PubMed1999

Optimization of cytochrome P4502D6 (CYP2D6) phenotype assignment using a genotyping algorithm based on allele frequency data.

Cytochrome P4502D6 (CYP2D6) is a highly polymorphic gene locus with > 50 variant alleles which lead to a wide range in enzymatic activity. So called poor metabolizers are carriers of any two non-functional alleles of the CYP2D6 gene. CYP2D6 genotyping is cumbersome and the question of how much genotyping is necessary for an accurate phenotype prediction is still debated. The goal of this study was to determine the optimum amount of genotyping required to accurately predict the phenotype at a reasonable cost in a white North American population. To address this issue, we designed a polymerase chain reaction (PCR)/restriction fragment length polymorphism-based genotyping strategy to detect 'key' mutations linked to extensive metabolizer or poor metabolizer associated alleles in combination with extra-long PCR (XL-PCR). All mutations with the exception of gene deletions and duplications are detectable by simple restriction digestion analysis and agarose gel electrophoresis. In addition, we utilized a genotyping algorithm based on our own and published allele frequency data and phenotype analysis to calculate the probability of a correct genotype (and thus, phenotype) assignment. As little as one XL-PCR reaction followed by a maximum of six reamplification reactions allows an accurate prediction of an individual's genotype to 99.15%. As few as four reamplification reactions identify 97.9% of poor metabolizer individuals. We evaluated our model in 208 white North Americans by testing for the presence of 'key' mutations linked to CYP2D6*2, *3, *4, *6, *7, *8, *9, *10, *11, *12, *15, *17 and *18 alleles and the *5, *13 and *16 gene deletions. For all individuals, the correct phenotype has been predicted. Discordant phenotype assignment occurred in only two individuals which subsequently was attributed to CYP2D6 inhibition by concomitant drug therapy.

Algorithms↗

PubMed1999

Limitations of dextromethorphan N-demethylation as a measure of CYP3A activity.

We evaluated the utility of the 3-methoxymorphinan/dextromethorphan (3MM/DM) urinary ratio to reflect baseline CYP3A activity, and its ability to discriminate moderate CYP3A inhibition during fluvoxamine therapy. For 4 months, oral dextromethorphan 30 mg and intravenous midazolam 0.025 mg/kg were administered to nine men every 14 days, and to 10 premenopausal women during the follicular and luteal phases of their menstrual cycles. Phenotyping during the first 3 months or cycles established baseline CYP3A activity. During the fourth month, individuals were given fluvoxamine 150 mg/day. CYP3A activity was expressed as both the urinary 3MM/DM molar ratio and midazolam plasma clearance (MDZ CL). 3MM/DM ratios were independent of dextromethorphan CYP2D6 phenotype (r = 0.13, P = 0.6). Intraindividual variability in baseline CYP3A activity (median, 25-75th percentile), as determined by coefficients of variation, was 48.3% (36.8-68.8%) for 3MM/DM and 10.3% (8.3-11.8%) for MDZ CL. No significant correlation between 3MM/DM and MDZ CL either at baseline (r = -0.22, P = 0.4) or during fluvoxamine therapy (r = -0.15, P = 0.6) was noted. With fluvoxamine 150 mg/day, median percentage change in the 3MM/DM ratios was -50.0% (-105.6-6.0%; P = 0.7), and median percentage change in MDZ CL was -33.7% (-27.0-39.3%; P < 0.0001). Only MDZ CL consistently indicated moderate inhibition of hepatic CYP3A activity. In addition, there was a lack of correlation between the magnitudes of fluvoxamine-induced change in 3MM/DM and MDZ CL (r = 0.41, P = 0.1). The large intraindividual variability of the 3MM/DM urinary ratio, as well as the inability to discriminate moderate CYP3A inhibition, makes this a suboptimal method for accurately assessing CYP3A activity.

Aryl Hydrocarbon Hydroxylases↗

PubMed1998

Chiral phase analysis of warfarin enantiomers in patient plasma in relation to CYP2C9 genotype.

A direct chiral-phase high-performance liquid chromatographic method for measuring the ratio of S-warfarin/R-warfarin in patient plasma is described. Plasma samples are first extracted using solid-phase C18 extraction columns, and the concentrated extracts analyzed using an (R,R) Whelk-O 1 column with a mobile phase of 0.5% glacial acetic acid in acetonitrile. The resulting chromatography provides baseline resolution of the warfarin enantiomers and internal standard (racemic ethylwarfarin), and is free from interference from other plasma components. Calibration curves were linear (mean r2 of 0.999 for both enantiomers) over the concentration range 0.25-1.5 microg/ml. The intra-day and inter-day coefficients of variation for analysis of plasma spiked with 0.33 microg/ml S-warfarin and 0.67 microg/ml R-warfarin (S/R=0.5:1) was less than 7% for each enantiomer, with an accuracy of more than 93%. Plasma extracts from thirty-one patients homozygous for wild-type CYP2C9*1 provided an S/R ratio of 0.51+/-0.15. Two warfarin patients homozygous for the mutant CYP2C9*2 and CYP2C9*3 alleles exhibited elevated S/R ratios relative to the mean for individuals homozygous for the wild-type CYP2C9*1 allele. This method is suitable for population studies aimed at establishing the effect of polymorphic expression of CYP2C9 alleles on S-warfarin elimination in humans.

Alleles↗

PubMed1998

Novel sulfotransferases cloned by RT-PCR: real proteins or PCR artifacts?

During studies designed to subclone human phenol sulfotransferase (STP and STM) sequences for use in heterologous E. coli-based expression systems, we designed two oligonucleotide primers that would allow for the simultaneous PCR amplification of expression cassettes containing the coding regions of the STP1, STP2 and STM cDNAs. Following total RNA isolation from human liver, reverse transcription of cDNA, PCR amplification under standard conditions, plasmid subcloning and restriction analysis to select for suitable ST recombinants, we recovered plasmids containing inserts corresponding to STP1, STP2 and STM. However, ten additional, closely related but apparently novel ST sequences were also isolated. Alignments of the three known ST sequences (and one published allelic variant) with these new clones revealed that each one appears to be a PCR-generated modular chimera possessing a combination of DNA segments derived from STP1, STP2 and STM. This observation should serve as an alert to the potential pitfalls of using PCR techniques for the cloning of highly related genes and their cDNA products, especially when PCR primer design allows for the amplification of multiple products in a single reaction.

Cloning, Molecular↗

PubMed1998

Bacterial expression of two human aryl sulfotransferases.

The effect of replacing a single codon in the N-terminal of human aryl sulfotransferase (HAST) 1 and 3 with one that is more commonly found in E. coli genes was assessed. The pKK233-2 E. coli expression vector was employed and the polymerase chain reaction (PCR) was used to introduce the 5' nucleotide substitution, at the same time maintaining the fidelity of the amino acid sequence. The data indicates that this change had a minimal effect on protein production, subcellular localization or, in the case of HAST3, catalytic activity. In general, the pKK233-2 E. coli vector has been less than optimal for expressing human sulfotransferase cDNAs.

Animals↗

PubMed1998

Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population.

The polymorphic cytochrome P450 CYP2D6 catalyses the biotransformation of at least 40 drugs. The CYP2D6 genetic polymorphism is responsible for pronounced interindividual differences in plasma concentrations and, hence, in drug action and side-effects after administration of the same dose. Provided there is a close relationship between CYP2D6 genotypes and catalytic function, genotyping could be used in the clinical setting for individualization of drug dose. In the present study, we evaluated the relationship between the in-vivo enzyme activity and 35 different genotypes in order to determine whether genotyping can be used to predict a person's metabolic capacity for CYP2D6-catalysed drug oxidation using sparteine as a probe drug. One hundred and ninety-five Caucasian individuals were genotyped for seven nonfunctional (CYP2D6 x 3, x 4, x 5, x 6, x 7, x 8, x 16) and eight functional alleles (CYP2D6 x 1, x 2, x 2 x 2, x 2B, x 2B x 2, x 9, x 10, x 17). The metabolic ratio distribution for sparteine showed trimodality, with 15 poor metabolizers, 21 intermediate metabolizers, and 1.59 extensive and ultrarapid metabolizers. All poor metabolizers were unambiguously identified as carriers of two nonfunctional alleles. In contrast, the most frequent functional genotypes extensively overlapped and, with few exceptions, genotype was not a useful predictor of function. Gene dose effects among homozygotes and heterozygotes of the major functional alleles were not significant and could not explain the wide variations. Only a minor fraction of phenotypical ultrarapid metabolizers, arbitrarily defined as individuals with a metabolic ratio < 0.2, could be identified as carriers of three functional gene copies, including duplicated CYP2D6 x 2 x 2 alleles. Similarly, only a minor fraction of the intermediate metabolizers had predictive genotypes involving alleles coding for enzyme with impaired function. Thus, genotyping correctly identifies poor metabolizers, but quantitative prediction of drug metabolism capacity among extensive metabolizers is not possible.

Adolescent↗

PubMed1998

Non-monooxygenase cytochromes P450 as potential human autoantigens in anticonvulsant hypersensitivity reactions.

Antibodies recognizing rat cytochrome P450 (CYP) 3A1 but not the closely related human CYPs 3A4/5 have been identified in the sera of patients with hypersensitivity reactions to phenytoin and carbamazepine. Comparison of the mapped epitope to the comparable region in CYP3A4 revealed that Leu361 was essential for antibody recognition because of L361V mutation (mimicking human EYLDMVVNETLRL) abolished immunoreactivity. To identify alternative human autoantigens, a site-directed mutagenesis strategy was employed to identify amino acids critical for antibody recognition. A protein database search with the consensus sequence, DxVLxETLxx, from immunoblot analysis produced CYP8 (prostacyclin synthase), CYP5A1 (thromboxane synthase), CYP27 and CYP7A1 (cholesterol 7 alpha-hydroxylase) as possible candidates; considerable homology was also observed with the fungal CYP52A subfamily. Immunoblotting with patient sera and fragments of each candidate autoantigen expressed as Escherichia coli gene 10 fusion proteins confirmed CYP8 and CYP5A1 as possible antigens, and revealed the presence of IgG1 and IgG3 antibodies against a construct mimicking fungal CYP52A10. All patient sera contained IgG4 antibodies against CYP8, CYP5A1 and the fungal mimic suggestive of continual antigenic challenge. In genetically susceptible individuals, prior infectious challenge may be a determinant of risk for the development of anticonvulsant hypersensitivity reactions and has been incorporated into a model investigating the pathogenesis of these events.

Amino Acid Sequence↗

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↗

PubMed1998

Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians.

The ability to metabolize CYP2D6 substrates sparteine, debrisoquine, and dextromethorphan was studied in healthy Caucasian (n = 20), Ghanaian (n = 21), and Chinese (n = 22) CYP2D6 extensive metabolizers. Genotype analysis for the CYP2D6*1, *3, *4, *5, *9, *10, and *17 alleles was performed. Interethnic differences in the disposition of the probe drugs were found among the extensive metabolizers; extensive metabolizer status was confirmed by phenotype and genotype analysis. The mean metabolic rate was lower for Caucasians than for Ghanaians for sparteine (P < 0.02) and for both Ghanaians and Chinese for debrisoquine (P < 0.02). Correlation comparisons resulted in lower pairwise correlation coefficients in Ghanaians compared with Chinese and Caucasians for every combination of probe substrates. In addition, in Chinese and Caucasians, metabolic rates for each pair of probe drugs were significantly correlated (P < 0.002), but in Ghanaians the dextromethorphan metabolic rates were not correlated to either sparteine or debrisoquine (P < 0.05). Even when only those with a CYP2D6*1/*1 genotype were included in the correlation calculations, the Ghanaians had very low correlation coefficients (r(s) - 0.02-0.2, n = 9); much lower than those found in Caucasian (r(s) 0.78-0.92, n = 14) or Chinese (r(s) 0.54-0.96, n = 7) individuals. Quinidine had significantly less affect on sparteine metabolic rates in Ghanaians than both Caucasians and Chinese (P < 0.02). In addition, five of the 21 Ghanaian individuals had dextromethorphan metabolic ratios which were unaffected by quinidine. These individuals also had differences in urinary recovery of dextromethorphan and its metabolites when compared to the other Ghanaian individuals. These results confirm the large ethnic differences in probe drug metabolism and quinidine sensitivity among these ethnic groups. They also suggest that the Ghanaians have an additional unidentified allele(s) with altered substrate specificity and quinidine sensitivity which is currently genotyped as CYP2D6*1.

Adult↗

PubMed1998

Quantification of intraindividual variability and the influence of menstrual cycle phase on CYP2D6 activity as measured by dextromethorphan phenotyping.

Intraindividual variability and the effects of menstrual cycle phase on CYP2D6 activity were evaluated by dextromethorphan phenotyping in 20 Caucasian normal volunteers. Dextromethorphan 30 mg was administered to 10 men every 14 days for 3 months, and to 10 premenopausal women during the mid-follicular and mid-luteal phases of each menstrual cycle for three complete cycles. Urinary dextromethorphan/dextrorphan molar ratios were obtained after an overnight urine collection. Ten women and nine men were extensive metabolizer phenotypes, and one man was a poor metabolizer phenotype (confirmed by genotyping). There was no difference in dextromethorphan metabolic ratios between the mid-follicular (mean +/- SD: 0.00728+/-0.00717) and mid-luteal (0.00745+/-0.00815) phases of the menstrual cycle (P = 0.88). Also, no significant difference was found in the intraindividual variability of the metabolic ratios between the two phases (P = 0.80). No statistically significant sex difference in CYP2D6 activity was found between men (0.00537+/-0.00431) and women (0.00737+/-0.00983) extensive metabolizers (P = 0.84). For all individuals, intraindividual variability in dextromethorphan ratios ranged from 12.1-136.6% with a median of 36.7%. Because hormonal fluctuations within the mid-follicular and mid-luteal phases of the menstrual cycle do not appear to affect CYP2D6 activity, pharmacokinetic or clinical investigations of CYP2D6 substrate activity may not require menstrual cycle phase stratification. Because baseline metabolic ratios may fluctuate an average of 37%, repeat baseline and treatment phenotyping assessments should be obtained for accurate determination of a given drug's effect on CYP2D6 activity when measured by dextromethorphan.

Adult↗

PubMed1998

High frequency of CYP2D6 poor and "intermediate" metabolizers in black populations: a review and preliminary data.

There is little and conflicting information concerning polymorphism of CYP2D6 in populations of Africans and African descent. Estimations of the prevalence of poor metabolizers (PMs) in Black populations have ranged from 0 to 19 percent, and unlike Caucasian and Asian populations, there seems to be a poor correlation in metabolic ratios (MRs) between commonly used CYP2D6 probe drugs. A novel mutant allele, CYP2D6*17, which is associated with reduced metabolic rates, has been determined to occur in high frequencies in African and African American populations. In the present pilot study, there was a high frequency of CYP2D6*17, and about one-third of the African-American participants showed a reduced capacity to metabolize dextromethorphan, a CYP2D6 probe drug. The CYP2D6*17 allele and other variants may possibly play a role in the inconsistent variation of phenotypes in Black populations.

Black People↗

PubMed1997

Human acetyltransferase polymorphisms.

Conjugation of primary amino and hydroxylamino groups with acetate, catalyzed by acetyl CoA-dependent arylamine acetyltransferase (NAT) enzymes, may play an important role in the intricate series of metabolic pathways that produce or prevent toxicity following exposure to homo- and heterocyclic arylamine and hydrazine xenobiotics. Two independently regulated and kinetically distinct human acetyltransferases are now known to exist, namely NAT1 and NAT2. Interindividual variation in NAT2 function is associated with the classical isoniazid acetylation polymorphism which was discovered over forty years ago. At last count, fifteen variant alleles at the NAT2 gene locus have been linked to the isoniazid 'acetylator phenotype', and each of these can be identified in population studies using specific PCR-based genotyping tests. On the other hand, NAT1 shows kinetic selectivity for compounds whose disposition is unrelated to the classical isoniazid acetylation polymorphism. NAT1 expression is also phenotypically variable in human populations, at least in part due to allelic differences at the NAT1 gene locus. Nine NAT1 variant alleles have been described to date, of which NAT1* 14 and NAT1* 15 clearly produce defective NAT1 proteins and lead to functional impairment in the metabolism of NAT1-selective substrates both in vivo and in vitro. On the other hand, it has been reported that the NAT1* 10 variant associates with elevated NAT1 activity and increased risk for cancers of the bladder and colon. Because of the important toxicologic consequences of allelic variation in NAT1 and NAT2 function for the metabolic activation of arylamine and heterocyclic amine procarcinogens, further studies are needed to improve our understanding of the extent of NAT allelic variation, to determine the functional capacity of each variant gene product, and to develop accurate methods of detecting them in population and epidemiological studies.

Acetylation↗