Krishan K. Kohli

CYP2C19 genetic mutations in North Indians

To identify defective alleles of CYP2C19 (CYP2C19*2 and *3) in North Indians.

Genetic polymorphism of the hepatic cytochrome P450 2C19 in North Indian subjects

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 μmol) 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.

Alterations in gallbladder emptying and bile retention in the absence of changes in bile lithogenicity in postmenopausal women on hormone replacement therapy.

The role of female sex hormones in the pathogenesis of gallstones is well established. Pregnancy, contraceptive use, estrogen replacement therapy in postmenopausal women, and estrogen therapy in men for the treatment of prostatic carcinoma have been found to be associated with increased risk of cholesterol gallstones. Alterations in gallbladder emptying and in bile lithogenicity in postmenopausal women receiving hormone replacement therapy (HRT) have not been studied to date. The present study was undertaken to study the effect of HRT on gallbladder emptying and bile lithogenicity. Sixteen postmenopausal women were included in the study. None of the patients had gallstone disease and none had received prokinetic drugs, such as, erythromycin, metoclopramide, domperidone or cisapride, aspirin, and nonsteroidal antiinflammatory drugs. Gallbladder emptying (n=16), bile microscopy (n=7), cholesterol saturation index (CSI) (n=7), and nucleation time (n=7) were studied before and 3 months after HRT (conjugated estrogen, 0.625 mg, + medroxyprogesterone acetate, 2.5 mg, everyday). Fasting and residual volumes increased (fasting volume, 18.2 ± 2.2 mL pre-HRT vs 27.6 ± 3.2 mL post-HRT, P = 0.0003; residual volume, 3.9 ± 0.6 mL pre-HRT vs 10.3 ± 2.0 mL post-HRT, P = 0.00009) and ejection fraction decreased (78.2 ± 2.5% pre-HRT vs 62.2 ± 3.8% post-HRT; P = 0.0017) after 3 months of HRT. There was no change in CSI (2.32 ± 0.36 pre-HRT vs 2.60 ± 0.51 post-HRT; P = NS) or in nucleation time (19.0 ± 1.2 days pre-HRT vs 17.6 ± 1.3 days post-HRT; P = NS). None of the bile samples either pre-HRT or post-HRT showed cholesterol monohydrate crystals. Though impairment of gallbladder emptying occurs in the short term with HRT in postmenopausal women, there is no change in CSI and nucleation time.

Obstetric cholestasis: Outcome with active management

To study the nature and clinical outcome of pregnancies with obstetric cholestasis on active management and to correlate perinatal outcome to gestational age at delivery.

Cisapride improves gallbladder emptying and bile lipid composition in patients with gallstones

Background and Aim: Biliary cholesterol supersaturation, gallbladder stasis and delayed intestinal transit are the key events in cholesterol gallstone formation. We studied the effect of cisapride, a prokinetic drug, on gallbladder emptying and bile composition in patients with gallstone disease undergoing cholecystectomy.

Association between urinary 6β-hydroxycortisol/cortisol ratio and CYP3A5 genotypes in a normotensive population

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.