Differences in the markers of oxidative stress and anti-oxidant status between NAFLD, CVH and healthy volunteers suggest presence of higher oxidative stress in patients with NAFLD.
CYP2C19*2 demonstrated allele frequency of 0.3, whereas CYP2C19*3 was absent in North Indians. Because CYP2C19*2 is not able to explain 57% of poor metabolizers, other mutations (CYP2C19*4 to *8) might be present in North Indians. CYP2C19 demonstrated differential evolution in North Indians because the frequency of CYP2C19*2 was similar to that in Oriental subjects, but that of CYP2C19*3 was similar to that in white subjects.
From this study, it can be concluded that the PM phenotype of CYP2D6 occurs with a frequency of 3% (95% confidence interval of 0.33%-6.33%) in North Indians.
We show that the CYP3A5*1/*3 polymorphism is an important determinant of the response to inhibition of tacrolimus metabolism by ketoconazole, with a 30% greater inhibition in those lacking *1 allele. This finding will allow better dose adjustment and minimize exposure to subtherapeutic or toxic concentrations.
One hundred unrelated healthy North Indian subjects were phenotyped with respect to their ability to metabolize omeprazole to 5-hydroxyomeprazole. Each volunteer was requested to ingest 20 mg (57.9 mumol) omeprazole. Urine was collected for a period of 8 hours and the amount of 5-hydroxyomeprazole excreted was estimated by HPLC. Histogram, probit, and normal test variable plots showed the antimode value for the log hydroxylation index of omeprazole to be 1.7. Of 100 North Indian subjects, 11 demonstrated log hydroxylation index values more than 1.7. Thus it is inferred that the frequency of occurrence of poor metabolizers of omeprazole in North Indian subjects is 11% (95% confidence interval, 5% to 17%). From the Hardy-Weinberg Law it was computed that the frequency of occurrence of the mutant allele of hepatic CYP2C19 in the North Indian subjects was 0.33.
Genetic polymorphism of genes involved in renal salt handling and arterial vessel tone is considered to be one of the causes of hypertension. Numerous reports suggest that cytochrome P4503A5 (CYP3A5) catalyzes 6β-hydroxylation of endogenous cortisol (CS), which is associated with sodium and water retention in the kidney and involved in the regulation of blood pressure. The purpose of the present study was to study the associations of single nucleotide polymorphisms in the CYP3A5 gene with the urinary 6β-hydroxycortisol/cortisol (6β-OH-CS/CS) ratio considered as quantitative phenotypes. CS measurements of three hundred (n=300) healthy, normotensive North Indian individuals was performed on morning spot urine samples by high-performance liquid chromatography. Furthermore, genotyping for CYP3A5*3 and CYP3A5*6 was performed by PCR-RFLP. The results indicated a unimodal distribution of CYP3A phenotypes in the North Indian population. In further analysis, all the phenotypes were distributed into three groups, demonstrating low (n=75), intermediate (n=150) and high CYP3A activity (n=75) based on CS and 6β-OH-CS levels and log 6β-OH-CS/CS ratios. The subjects in the low and high activity groups were genotyped for the CYP3A5*3 and *6 alleles. The present study demonstrated that the allele frequencies of CYP3A5*1 and *3 were 0.29 (95% CI, 0.22–0.36) and 0.71 (95% CI, 0.64–0.78), respectively. Notably, the frequency of normal homozygotes (CYP3A5*1/*1) was significantly higher in the high activity than the low activity group (11% vs. 5%). Similarly, the frequency of mutant homozygotes (CYP3A5*3/*3) was significantly higher in the low activity group than the high activity group (57% vs. 44%). The allele frequency of CYP3A5*3 was significantly higher in the low activity group (0.76) than the high activity group (0.67). The mean 6β-OH-CS/CS ratios were 110, 76 and 69 in wild-type homozygotes (n=12), heterozygotes (n=62) and mutant homozygotes (n=76), respectively. The difference between the normal and mutant homozygotes was statistically significant (P<0.05). The CYP3A5*6 allele was absent from all the subjects genotyped. This is the first study to report the genetic polymorphism of CYP3A5 in a North Indian population and its association with urinary 6β-OH-CS/CS ratio reflecting the CYP3A phenotypes.
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