CYP3A phenotypes and genotypes in North Indians

Rais, Naushad; Chawla, Yogesh; Kohli, Krishan K.

doi:10.1007/s00228-006-0105-3

Cited by 25 publications

(16 citation statements)

References 38 publications

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“…In our study, no signiﬁcant allele frequency was observed for the CYP3A4 polymorphism, even though a genotypic association for CYP3A4*4 and *5 between patients and controls was found. This is in accordance with a genotype and phenotype study done in a North Indian population which demonstrated the absence of CYP3A in North Indians on the basis of frequency distribution of the urinary 6β-OH-CS/CS ratio and the absence of the variant alleles CYP3A4*2, *4, *5, *6 and *10, which are common in other ethnic groups [27]. Incidences of these mutations in Chinese subjects are rare [9].…”

Section: Discussionmentioning

confidence: 56%

Impact of CYP2D6 and CYP3A4 Genetic Polymorphism on Combined Cholinesterase Inhibitors and Memantine Treatment in Mild to Moderate Alzheimer's Disease

Nirmal

Tripathi²,

Sagar³

et al. 2013

Dement Geriatr Cogn Disord

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Aim: The impact of CYP2D6 and CYP3A4 polymorphism on the steady-state plasma concentrations and therapeutic outcome of donepezil monotherapy and combination therapy in Alzheimer's disease (AD) patients. Methods: A total of 38 patients for donepezil and 17 patients for donepezil and memantine therapy, aged ≥55 years, were recruited meeting inclusion and exclusion criteria. Polymerase chain reaction-restriction fragment length polymorphism was performed. The liquid chromatography-tandem mass spectrometry method was used for estimation of drug levels of donepezil and memantine. Results: Significant allele frequency was observed for CYP2D6*3 polymorphism in patients on donepezil monotherapy and combination therapy. Significant allele frequency for CYP2D6*4 was observed in the patients on donepezil monotherapy. Conclusion: CYP2D6 polymorphism, though not significant, might partially be involved in the plasma concentration of AD drug.

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Section: Discussionmentioning

confidence: 56%

Impact of CYP2D6 and CYP3A4 Genetic Polymorphism on Combined Cholinesterase Inhibitors and Memantine Treatment in Mild to Moderate Alzheimer's Disease

Nirmal

Tripathi²,

Sagar³

et al. 2013

Dement Geriatr Cogn Disord

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“…The probe-drug activity of compounds such as erythromycin, midazolam, endogenous cortisol, and testosterone has been already established. 11) Although those compounds have high specificity for measurement of CYP3A activity, difficulties in finding an ideal probe remain due to differences in enzyme activity in organs such as the liver, intestines, and kidney; the overlap of substrate specificity with P-glycoprotein and other CYP enzymes; high interindividual proband variability; and possible low affinity of the enzyme for probe drugs. In addition, these probes require invasive methods to administer the drug and collect the samples.…”

Section: Discussionmentioning

confidence: 99%

“…9) Probe drugs including midazolam, erythromycin, nifedipine, lidocaine, and dextromethorphan and endogenous compounds such as cortisol and testosterone have been utilized to evaluate CYP3A activity. 10,11) Watkins 12) proposed three specific CYP3A probes: erythromycin; midazolam; and cortisol. However, the probe drugs available for accurate, safe, and easy measurement of CYP3A activity remain limited.…”

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confidence: 99%

Potential of Lansoprazole as a Novel Probe for Cytochrome P450 3A Activity by Measuring Lansoprazole Sulfone in Human Liver Microsomes

Yanagida

Watanabe

Takeba

et al. 2009

Biological & Pharmaceutical Bulletin

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Cytochrome P450 (CYP) 3A is the primary CYP isoenzyme subfamily responsible for phase I metabolism of Ͼ50% of drug doses administered to humans.1,2) CYP3A4 is the most prominent CYP in humans, comprising about 30% and 70% of total CYP in the liver and intestine, respectively. CYP3A has very broad substrate specificity, encompassing a wide variety of therapeutic agents.3) Many cancer chemotherapeutic agents such as vinca alkaloids, paclitaxel, irinotecan hydrochloride and other widely used drugs such as amiodarone, diltiazem, lovastatin, erythromycin, and midazolam are substrates for CYP3A. [4][5][6][7] Recently, individual variations in CYP3A activity in the human liver have been reported. 8)Because the pharmacokinetics of various drugs is influenced by individual variations in CYP3A activity, it is important to evaluate those variations in the clinical setting to achieve the optimum therapeutic outcomes. 9)Probe drugs including midazolam, erythromycin, nifedipine, lidocaine, and dextromethorphan and endogenous compounds such as cortisol and testosterone have been utilized to evaluate CYP3A activity.10,11) Watkins 12) proposed three specific CYP3A probes: erythromycin; midazolam; and cortisol. However, the probe drugs available for accurate, safe, and easy measurement of CYP3A activity remain limited.Lansoprazolebenzimidazole, is a proton-pump inhibitor (PPI) that suppresses gastric acid secretion by inhibiting (H ϩ /K ϩ )-ATPase and is prescribed commonly for the treatment of gastric ulcer, reflux esophagitis, etc., with few serious side effects reported. Following administration, lansoprazole is extensively metabolized to 5-hydroxylansoprazole and lansoprazole sulfone (LS) by CYP2C19 and CYP3A, respectively. 13) Masa et al. 14) reported that the metabolism to LS by CYP3A occurs independently of that to 5-hydroxylansoprazole by CYP2C19 in the human liver. Inhibition of one metabolic pathway caused by the genetic polymorphisms of CYPs leads to upregulation of another pathway in vivo. To use lansoprazole as probe drug, these problems should be elucidated in vitro or in vivo. The present study investigated the utility of lansoprazole in assessing CYP3A activity in comparison with previously reported in vitro methods. Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan: and b Research Laboratories, HAB Research Organization; 3rd Floor, Cornea Center Bldg., Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa, Chiba 272-8523, Japan. Received April 13, 2009; accepted May 15, 2009; published online June 1, 2009 Cytochrome P450 (CYP) 3A enzymes are responsible for the metabolism of many drugs. It is useful to know CYP3A activity in individual patients undergoing drug therapy so as to predict the efficacies or adverse events. Lansoprazole is metabolized to Lansoprazole sulfone (LS) by CYP3A, while to 5-hydroxylansoprasole by CYP2C19. The aim of this study was to evaluate whether lansoprazole can be used to assess CYP 3A activity in human liver. Lansoprazole sulfoxidation activity in 14 human liver microsomes was det...

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“…A total of 300 North Indian individuals were phenotyped for CYP3A by measuring CS and 6β-OH-CS levels in urine by HPLC as described previously (16). …”

Section: Methodsmentioning

confidence: 99%

“…However, reports concerning the association of CYP3A5 genetic polymorphism with BP or hypertension have been largely inconsistent in humans (11–15). We have previously reported the absence of CYP3A4 genetic polymorphism in North Indian individuals and its correlation with the urinary 6β-hydroxy cortisol/cortisol (6β-OH-CS/CS) ratio (16). …”

Section: Introductionmentioning

confidence: 99%

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

Rais¹,

Hussain²,

Chawla

et al. 2012

Experimental and Therapeutic Medicine

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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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CYP3A phenotypes and genotypes in North Indians

Abstract: This is the first investigation establishing CYP3A phenotypes and demonstrating the absence of common CYP3A4 genotypes in North Indians.

Cited by 25 publications

References 38 publications

Impact of CYP2D6 and CYP3A4 Genetic Polymorphism on Combined Cholinesterase Inhibitors and Memantine Treatment in Mild to Moderate Alzheimer's Disease

Impact of CYP2D6 and CYP3A4 Genetic Polymorphism on Combined Cholinesterase Inhibitors and Memantine Treatment in Mild to Moderate Alzheimer's Disease

Potential of Lansoprazole as a Novel Probe for Cytochrome P450 3A Activity by Measuring Lansoprazole Sulfone in Human Liver Microsomes

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

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