CYP2D6 genotype and phenotype relationship in South Indians.

BACKGROUND: Genotypes of the drug-metabolizing enzyme CYP2D6 influence plasma levels of 25% of commonly prescribed drugs. This is the first study in India to investigate the genotype-phenotype relationship of CYP2D6. AIM: To study the influence of some CYP2D6 genotypes on the metabolism of its substrate dextromethorphan in healthy South Indian volunteers and to assess the contribution of the CYP2D6*10 and CYP2D6*4 alleles. MATERIALS AND METHODS: Twenty-six subjects from a previous CYP2D6 genotyping study of healthy volunteers were included for phenotyping in this study. Selected volunteers belonged to any one of three genotype groups:Group I - two normal activity alleles, Group II - one reduced activity allele and one normal activity allele and Group III - one loss of function allele along with either a wild type or reduced activity allele. Volunteers were phenotyped for the CYP2D6 enzyme using dextromethorphan as probe drug. Concentrations of the parent drug and metabolite dextrorphan were estimated using high performance liquid chromatography. Metabolic ratios were calculated as the ratio of parent drug to metabolite in 0-8h urine samples. STATISTICAL ANALYSIS: Metabolic ratios from each genotype group were compared using the Mann-Whitney test at 5% significance, to observe their difference between genotype groups. RESULTS: The mean metabolic ratios+/-SD in Groups I, II and III were 0.0039+/-0.0031, 0.0032+/-0.0017 and 0.0391+/-0.0331 respectively. The mean metabolic ratio of Group III was significantly higher when compared with Groups I or II. In heterozygous individuals, the *1 or *2 alleles compensated for the reduced enzyme activity due to the *10 allele. However, if a heterozygous individual had a *4 allele, the reduced enzyme activity could not be compensated by the *1 or *2 alleles. CONCLUSIONS: The CYP2D6 enzyme activity was found to be decreased in individuals carrying *4 or *5 alleles. The *1 or *2 allele could compensate for the reduced function due to *10 allele, but not for the loss of function due to *4 allele.

Glutathione S-transferase M1 and T1 null genotype distribution in South Indians.

OBJECTIVE: To investigate the distribution of the homozygous null genotypes of GSTM1 and GSTT1 in the South Indian population. METHODS: Five hundred and seventeen unrelated natives of the South Indian states of Tamilnadu and Pondicherry (n=170), Kerala (n=122), Karnataka (n=110) and Andhra Pradesh (n=115) were analyzed for homozygous deletions of GSTM1 and GSTT1. A multiplex polymerase chain reaction method simultaneously detected both GSTM1 and GSTT1 homozygous null genotypes. The observed frequencies from the four groups were compared statistically with each other and the combined frequencies were compared with frequencies of other major populations previously reported in the literature. RESULTS: In South India, 30.4% (95% CI 26.4-34.3) lacked the GSTM1 gene, 16.8% (13.6-20.1) lacked the GSTT1 gene and 4.6% (3.0-6.8) lacked both the GSTM1 and GSTT1 genes. The highest frequency of GSTM1 null was observed in Karnataka (36.4%, 27.4-45.4), while Andhra Pradesh had the lowest frequency of the GSTM1 and GSTT1 combined double-null genotypes (1.7%, 0.21-6.2). CONCLUSION: The prevalence of the GSTM1 null genotype differed within India. The frequency of GSTM1 null in South Indians was significantly lower than that in Caucasians. The frequencies of both GSTM1 and GSTT1 null genotypes in South Indians were significantly lower than in the Japanese.

Genotype and allele frequency of CYP2D6 in Tamilian population.

OBJECTIVE: To assess the frequency of CYP2D6 *3, *4, *5 and *10 allelic variants in a South Indian population and compare the frequencies with other major populations. METHODS: Polymerase chain reaction (PCR) or PCR-restriction fragment length polymorphism (RFLP)-based methods were used to identify the CYP2D6 genotypes of 106 healthy unrelated male and female volunteers of Tamilian origin. The allele and genotype frequencies observed were compared with other major populations. RESULTS: The *10 allele was the most frequent mutant allele in Tamilians (20.3%). The *5 allele occurred at 0.9% and the *3 allele was not detected. The most frequent allele causing enzyme inactivation was *4 allele in Tamilians (6.6%), which is significantly higher than that reported in Japanese (0%). CONCLUSIONS: The *10 allele is the most common mutant allele in Tamilians. The CYP2D6*4 and CYP2D6*5 alleles are distributed in a significantly different way in the Tamil population relative to Oriental populations.