Importance of CYP2C19 genetic polymorphism in the eradication of Helicobacter pylori in north Indians.

Background & objectives: Genetic polymorphism of CYP2C19 is known to occur with a frequency of 12 per cent in north Indian population. But no study correlated CYP2C19 genetic polymorphism with eradication of Helicobacter pylori in north Indian gastritis patients positive for H. pylori and hence this study. Methods: Ninety one consecutive patients positive for H. pylori fulfilling the study criteria were phenotyped and genotyped for CYP2C19. They were given 20 mg omeprazole (OPZ), 750 mg amoxicillin (AMC) and 500 mg tinidazole (TNZ) (bid) for 7 days followed by 20 mg OPZ (qd) for 21 days. Non eradicated extensive metabolizers (EMs) were retreated with 40 mg OPZ (bid) and 500 mg AMC (qid) for 14 days. Results: EMs and poor metabolizers (PMs) excreted 4.26 ± 0.34 (95% CI 3.59-4.92) and 0.73 ± 0.05 (95% CI 0.63-0.82) μmol 5-OH-OPZ in 8 h, respectively. After initial therapy, EMs demonstrated 37 per cent (95% CI: 24.5-49.5) and PMs 92 per cent (95% CI: 77-107) eradication of H. pylori. Non eradicated EMs after retreatment demonstrated 90 per cent (95% CI: 79-101) eradication. Interpretation & conclusions: This study demonstrated a direct correlation between CYP2C19 genetic polymorphism and H. pylori eradication in north Indian patients with gastritis. Knowing the CYP2C19 phenotype of a patient may help in prescribing optimum dose of proton pump inhibitor to achieve better therapeutic outcome.

Genetic polymorphism of CYP2C19 & therapeutic response to proton pump inhibitors.

Proton pump inhibitors (PPIs) are extensively metabolized in the liver by CYP2C19, that demonstrates genetic polymorphism with 21 mutant alleles. The subjects can be divided into 2 groups with respect to CYP2C19 phenotypes viz., extensive metabolizers (EMs) and poor metabolizers (PMs) of PPIs. This division results in marked interindividual variations in the pharmacokinetics and pharmacodynamics of PPIs in the population. Intragastric pH values and the plasma concentration of PPIs after oral ingestion were significantly lower in EMs namely normal homozygotes (CYP2C19*1/*1) and heterozygotes (CYP2C19*1/*X) compared to PMs namely mutant homozygotes (CYP2C19*X/*X) where 'X' represents the mutant allele. Hence, association has been found between the genetic polymorphism of CYP2C19 and therapeutic response to PPIs. CYP2C19 polymorphism affected eradication of Helicobacter pylori using diferent PPI based eradication therapies as PM patients demonstrated significantly higher eradication rates compared to EMs. CYP2C19 genetic polymorphism also affects the therapeutic outcome of gastroesophageal reflux disease (GERD), reflux oesophagitis and duodenal ulcers. For optimal therapeutic response with PPIs, CYP2C19 pharmacogenetics should be taken into consideration. This shall help in the prescription of optimal doses of PPIs, thus paving the way for personalized medication.

Purification of catalytically active hepatic NADPH cytochrome P450 oxidoreductase from the rhesus monkey, Macaca mulatta.

Hepatic NADPH cytochrome P450 oxidoreductase capable of supporting polysubstrate monooxygenase (PSMO) reactions was purified from microsomes obtained from phenobarbitone (PB) pretreated rhesus monkey. Two preparations of the enzyme purified by affinity and molecular exclusion chromatographic techniques demonstrated specific content of 19.5 and 37.9 nmol cytochrome c reduced/min/mg protein and subunit molecular weight of 66 and 80 kDa, respectively. Both forms supported oxidation of NADPH and reduction of cytochrome c and DCIP but only 80 kDa preparation supported PSMO reactions. The reconstituted system consisted of hepatic P450, NADPH cytochrome P450 oxidoreductase, cytochrome b5 all purified from PB pretreated rhesus monkey and dilauroyl phosphatidylcholine or microsomal lipid. Eighty kDa preparation supported the metabolism of aminopyrine and tolbutamide by hepatic P4502C and erythromycin, ethylmorphine and nifedipine by hepatic P450 3A, respectively. The turnover of these substrates increased in the presence of partially purified cytochrome b5 from the rhesus monkey. To best of our knowledge this is the first report on the purification of monkey hepatic NADPH cytochrome P450 oxidoreductase capable of supporting in vitro PSMO by different isozymes of P450.

Gene regulation of cytochrome P450--an overview.

Xenobiotics have played a role in elucidating the regulation of gene expression of hepatic cytochrome P450 in the eukaryotes. The major regulation of P450 genes in the eukaryotes is at the transcriptional and post transcriptional level. Polycyclic aromatic hydrocarbons regulate the gene expression by binding the cytosolic aryl hydrocarbon receptor and its translocation to the nucleus where it forms a ternary complex with aryl hydrocarbon nuclear translocator. The ternary complex PAH-AHR-ARNT acts as a transcription factor and binds aromatic hydrocarbon responsive element to increase the expression of CYP1A1 gene. Phenobarbitone and ethanol regulate the expression of respective P450s within CYP2 gene family by different mechanisms but without the involvement of a cytosolic receptor. PB uses phosphorylation as a switch to increase the affinity of the transcription factor(s) for the positive rather than negative PB regulatory element within CYP2B1/2. This is one of the novel ways that nature has designed for a protein to act as a negative as well as a positive acting transcription factor. Ethanol regulates the expression of CYP2E1 by posttranslational stabilization making it resistant to the proteolytic digestion. Steroids regulate expression of CYP3A genes through a receptor mediated mechanism. The binary complex of the steroid and its receptor increases the transcription of CYP3 genes by binding glucocorticoid responsive element which is already occupied by another protein. Peroxisome proliferators also follow a receptor mediated mechanism in which a binary complex of PP activated receptor and retinoid X receptor acts a transcription factor and increases the expression of CYP4A genes by binding peroxisome proliferator responsive element. These studies demonstrate that PAH, glucocorticoids and PP follow a receptor mediated whereas PB and ethanol follow a nonreceptor mediated mechanism for the regulation of respective P450 genes in the eukaryotes.

Perioperative myocardial infarction in coronary artery disease patients and 'at-risk' for coronary artery disease patients undergoing non-cardiac surgery.

BACKGROUND: Perioperative myocardial infarction (POMI) carries a high mortality and occurs more commonly in patients with a history of coronary artery disease (CAD). However, there are also other patients undergoing surgery who are 'at risk' for CAD but who do not have a history of infarction or angina. We compared the incidence of POMI in these two groups. METHODS: In a prospective study of 69 men and 39 women over 30 years of age undergoing non-cardiac surgery under general or regional anaesthesia, 56 had definite CAD and 52 were 'at-risk' for CAD. All these patients were followed up with serial postoperative electrocardiography and CK-MB isoenzyme analysis for the diagnosis of POMI. RESULTS: The POMI rate was 32% in definite CAD patients and 15% in patients 'at-risk' for CAD. Mortality in patients with POMI was 17% in those with CAD and 13% in those 'at-risk' for CAD. Perioperative myocardial infarction was maximal in the first 24 hours following surgery (77%). All the POMIs were painless. Anaesthesia techniques--whether regional or general--did not influence the incidence of POMI (Chi-square, p > 0.05). The type of drugs used in the treatment of CAD such as beta-blockers, calcium channel blockers and antiplatelet agents did not cause any difference in the incidence of POMI (Chi-square, p > 0.05). Patients who had either an intraoperative hypertensive episode, tachycardia, arrhythmias or ST-segment changes had a higher incidence of POMI (Chi-square, p > 0.05). The incidence of POMI was not lower in patients undergoing transurethral resection of the prostate compared to patients undergoing other types of non-cardiac surgery (Chi-square, p > 0.05). CONCLUSION: POMI occurs in one-third of patients with a history of CAD and one-sixth of those 'at-risk'. It carries a mortality of 17% and 13% respectively. Decisions to operate on such patients should be taken with caution.