CYP2C19 Enzyme Activity Research Articles

CYP2C9 gene and susceptibility to major depressive disorder

Alteration of monoaminergic neurotransmission has been implicated in the pathophysiology of mood disorders, and CYP2C9 enzyme activity has been shown to be modulated by serotonin in vitro. The present study was aimed at analysing the frequency of CYP2C9 alleles (*1, *2, *3) among patients suffering from major depressive disorder. In all, 70 such suffering psychiatric outpatients were studied. The CYP2C9 genotypes were determined by allele-specific PCR. The CYP2C9*3 allele frequency was higher (P<0.01) among the patients suffering from major depression than in a population of 89 schizophrenic patients (odds ratio=3.3) and 138 healthy volunteers (odds ratio=2.8). The results suggest that CYP2C9 genetic polymorphism may be related to a major depressive disorder due to an alteration in endogenous metabolism, although a linkage between CYP2C9 and some other gene related to depression cannot be ruled out.

Bioinformatics Research on Inter-racial Difference in Drug Metabolism II. Analysis on Relationship between Enzyme Activities of CYP2D6 and CYP2C19 and their Relevant Genotypes

The enzyme activities of CYP2D6 and CYP2C19 show a genetic polymorphism, and the frequency of poor metabolizers (PMs) on these enzymes depends on races. We have analyzed frequencies of mutant alleles and PMs based on the published data in previous study (Shimizu, T. et al.: Bioinformatics research on inter-racial difference in drug metabolism, I. Analysis on frequencies of mutant alleles and poor metabolizers on CYP2D6 and CYP2C19.). The study shows that there were racial differences in the frequencies of each mutant allele and PMs. In the present study, the correlation between genotypes and drug-metabolizing enzyme activities was investigated. The result showed that enzyme activities varied according to the genotypes of subjects even in the same race. On the other hand, if subjects had the same genotypes, almost no racial differences were observed in drug-metabolizing enzyme activities. From these results, it was supposed that the racial differences in activities of these enzymes could be explained by the differences in distribution of genotypes. It would be possible to explain the racial differences in drug-metabolizing enzyme activities based on the differences on individual pharmacogenetic background information, not merely by comparison of frameworks such as races and nations.

Bioinformatics Research on Inter-racial Difference in Drug Metabolism I. Analysis on Frequencies of Mutant Alleles and Poor Metabolizers on CYP2D6 and CYP2C19

The enzyme activities of CYP2D6 and CYP2C19 show a genetic polymorphism, and the frequency of poor metabolizers (PMs) on these enzymes depends on races. In the present study, the frequencies of mutant alleles and PMs in each race were analyzed based on information from published studies, considering the genetic polymorphisms of CYP2D6 and CYP2C19 as the causal factors of racial and inter-individual differences in pharmacokinetics. As a result, it was shown that there were racial differences in the frequencies of each mutant allele and PMs. The frequencies of PMs on CYP2D6 are 1.9% of Asians and 7.7% of Caucasians, and those of PMs on CYP2C19 are 15.8% of Asians and 2.2% of Caucasians. Based on the results, it was suggested that there would be racial differences in the frequencies of PM subjects whose blood concentrations might be higher for drugs metabolized by these enzymes. Additionally, it was suggested that enzyme activities would vary according to the number of functional alleles even in subjects judged to be extensive metabolizers (EMs). In the bridging study, genetic information regarding CYP2D6 and CYP2C19 of the subjects will help extrapolate foreign clinical data to a domestic population.

Association of CYP2C9 genotypes leading to high enzyme activity and colorectal cancer risk.

CYP2C9 enzyme activity is involved in the metabolism of substances related to colorectal cancer, and it is functionally linked to a genetic polymorphism. Two allelic variants of the CYP2C9 gene, namely CYP2C9*2 and CYP2C9*3, differ from wild-type CYP2C9*1 by single amino acid substitutions. These mutated alleles encode enzymes with altered properties that are associated with impaired metabolism. The present study evaluates the impact of CYP2C9 genotypes leading to high enzyme activity on colorectal cancer risk. For this, the frequency of allelic variants of the CYP2C9 gene was analysed in genomic DNA from 129 patients with colorectal cancer and in 150 healthy controls. Patients with colorectal cancer showed a statistically significant increase in the frequency of genotypes homozygous for the active CYP2C9*1 gene, as compared with healthy individuals. Such a high frequency is more significant among patients with cancer in proximal segments of the colon (P < 0.025; odds ratio 2.36 95% CI 1.18-4.72), and decreases in more distal tumour locations. We conclude that CYP2C9 polymorphism can be considered as a secondary risk factor for colorectal cancer in the studied population: those individuals with genotypes leading to high enzyme activity were at increased risk. The association of the CYP2C9 polymorphism to colorectal cancer risk could be related to CYP2C9-mediated metabolic activation of polycyclic aromatic hydrocarbons and heterocyclic aromatic amines. In addition, the key role of CYP2C9 in the metabolic inactivation of non-steroidal anti- inflammatory drugs could diminish the protective effect of these drugs against colorectal cancer.

Evidence for the effect of gender on activity of (S)-mephenytoin 4???-hydroxylase (CYP2C19) in a Chinese population

There is evidence that the sex-dependent expression of individual forms of the human cytochrome P450s (CYPs) results in gender-related differences in the hepatic metabolism of certain drugs. Previous work has shown that conflicting evidence exists relating to the sex differences in the activity of (S)-mephenytoin 4'-hydroxylase (CYP2C19). Accordingly, we assessed the effect of gender on CYP2C19 activity in a phenotyped and genotyped healthy unrelated Chinese population for further evidence of such a gender-based differentiation. One hundred and sixteen females and 129 males took one tablet of 100 mg racemic mephenytoin (Mesantoin, Sandoz) after emptying their urinary bladders. Amounts of (S)- and (R)-mephenytoin and its metabolite 4'-hydroxymephenytoin (4'-OH-M) excreted in the postdose 0-8 h urine collection were determined by GC and HPLC methods, respectively. The CYP2C19 activity was expressed as the ratio of S/R-mephenytoin (S/R-ratio), the percentage of the dose excreted as 4'-OH-M (D%), and the log10 of the hydroxylation index which was defined as the ratio of micromoles of (S)-mephenytoin dose to micromoles of 4'-OH-M excreted in urine (1g HI). From all the subjects studied, 53 extensive metabolizers (EMs) and 19 poor metabolizers (PMs) phenotyped were randomly selected and the DNA extracted from their blood samples was utilized for genotyping analysis according to the previously developed standard procedures. In this population, the phenotype PMs were identified in 10.9% (14/128) of the males, as compared with 11.2% (13/116) of the females (chi 2 = 0.0045, df = 1; p > 0.05). In all phenotyped subjects, the S/R-ratio of EM males was significantly higher than that of EM females (mean +/- SD; 0.28 +/- 0.17 vs. 0.24 +/- 0.15; p = 0.030), but no sexual differentiation was observed (p > 0.05) in 4'-OH-M excreted among all EMs and PMs, or the S/R-ratio among all PMs. In all genotyped EMs, the frequency of homozygous EMs was 18.4% higher in females (51.7%, 15/29) than in males (33.3%, 8/24) although there was no significant difference (chi 2 = 1.1370, df = 1, p > 0.05), but the S/R-ratio was lower in homozygous females than in homozygous males (0.22 +/- 0.14 vs. 0.33 +/- 0.09; p = 0.046). Thus, we conclude that the higher CYP2C19 activity in females exists among both the phenotyped EMs and the genotyped homozygous EMs compared with that in males, and that the defect frequency of the enzyme activity is equal between the genders. We also conclude that the S/R-ratio is more a sensitive metabolic marker of CYP2C19 enzyme activity than the D% and 1g HI.

Genotype analysis of the CYP2C19 gene in the Japanese population.

A polymorphic CYP2C19 gene was analyzed in 233 Japanese subjects, including 63 with Parkinson's disease, 92 with chronic liver diseases (35 chronic hepatitis, 19 liver cirrhosis, 16 hepatocellular carcinoma, 10 primary biliary cirrhosis and 12 autoimmune hepatitis), 14 with lung cancer (squamous cell carcinoma) and 64 healthy subjects to determine the genotype distributions of the CYP2C19 gene and to investigate its involvement in the diseases. Among Japanese healthy subjects 14.1% are predicted to be poor metabolizers (PM) of mephenytoin. The frequencies of the m1 and the m2 mutations of the CYP2C19 gene in the healthy subjects were 21.9% and 11.7%, respectively. Though the number of patients was small, patients with lung cancer (squamous cell carcinoma) are believed to have reduced enzyme activities of CYP2C19.