CYP2C19 pharmacogenetics in advanced cancer: compromised function independent of genotype

CYP2C19 is a drug-metabolising enzyme involved in the metabolism of a number of chemotherapeutic agents including cyclophosphamide. Variants of the CYP2C19 gene result in a loss of function polymorphism, which affects approximately 3% of the Caucasian population. These individuals are poor metabolisers (PM) of a wide range of medications including omeprazole (OMP). In healthy subjects PM can be identified through homozygous variant genotype. However, a discordance between CYP2C19 genotype and phenotype has been reported previously in a small study of cancer patients. To investigate whether CYP2C19 activity was decreased in patients with advanced cancer, CYP2C19 genotype was determined in 33 advanced cancer patients using PCR-RFLP analysis for the two important allelic variants (*2,681G>A and *3,636G>A) and the activity of the enzyme was evaluated using the CYP2C19 probe drug OMP. The activity of the drug-metabolising enzyme CYP2C19 was severely compromised in advanced cancer patients, resulting in a PM status in 37% of the patients who had normal genotype. This is significantly (P<0.0005) higher than that would be predicted from the genotypic status of these patients. There was no evidence of a correlation between compromised CYP2C19 activity and any of the proinflammatory cytokines or acute phase response proteins studied. However, there was preliminary evidence of an association between PM status and low body mass (P=0.03). There is increasing interest in using pharmacogenetics to ‘individualise medicine', however, the results of this study indicate that in a cancer population genotyping for CYP2C19 would significantly underestimate the number of phenotypic PM of drugs, such as cyclophosphamide, which may be metabolised by this enzyme

Association of the DRD2 TaqIA, 5-HT1B A-161T, and CNR1 1359 G/A Polymorphisms with Alcohol Dependence

Objective: Alcohol dependence is associated with genetic variants of alcohol-metabolizing enzymes and genes related to dopaminergic, gamma-aminobutyric acidergic, glutamatergic, opioid, cholinergic, and serotonergic systems. Genetic variations in the endogenous cannabinoid system are also involved in alcohol dependence. The present study aimed to evaluate the association between three polymorphisms, DRD2 TaqIA, 5-HT1B A-161T and CNR1 1359 G/A (rs1049353), and alcohol dependence.Methods: One hundred twenty three patients, who were diagnosed as having alcohol dependence according to the DSM-IV criteria and 125 healthy volunteers, were included in the study. With written informed consent, a blood sample was drawn from each individual. Venous blood samples were collected in ethylenediaminetetra acetic acid (EDTA) containing tubes. DNA was extracted from whole blood by the salting out procedure. Genetic analyses were performed as described in the literature by using a Polymerase Chain Reaction method. SPS5 17.0 software was used for statistical analysis.Results: The DRD2 TaglA polymorphism was analyzed in the study and control groups. In the study group, the All A1 genotype was observed in 5 (4.0%) patients, the A1/A2 genotype was observed in 51 (41.5%) patients and the A2/A2 genotype was observed in 67 (54.5%) patients. In the control group, the A1/A1 genotype was observed in 6 (4.8%) subjects, the A1/A2 genotype was observed in 40 (32.0%) subjects and the A2/A2 genotype was observed in 79 (62.2%) subjects. For the 5-HT1B receptor A-161T gene polymorphism, the A/A genotype was detected in 61(49.6%) patients, the Ail genotype was detected in 53 (43.1%) and the T/T genotype was detected in 9 (7.3%) patients. In the control group, the A/A genotype was detected in 84 (67.2%) subjects, the All genotype was detected in 39 (31.2%) subjects, and the T/T genotype was detected only in 2 (1.6%) subjects. The G/G genotype was the most common genotype in both study and control groups for CNR1 1359 gene polymorphism. It was detected in 75 (61.0%) study patients and in 84 (67.2%) control subjects. The G/A genotype was observed in 39 (31.7%) patients of the study group and 38 (30.4%) subjects of the control group. The A/A genotype was the most rare genotype in both groups; it was detected only in 9 (7.3%) study patients and 3 (2.4%) control subjects. Of the three polymorphisms investigated, 5-HT1B A-1 61T was the only one found to be associated with alcohol dependence.Conclusions: The 5-HT1B receptor A-161T polymorphism might be a promising marker for alcohol dependence