Genetic polymorphisms of CYP2E1, GST, and NAT2 enzymes are not associated with risk of breast cancer in a sample of Lebanese women.

Changes in the activity of drug metabolizing enzymes (DMEs) are potentially associated with cancer risk. This relationship is attributed to their involvement in the bioactivation of multiple procarcinogens or the metabolism of multiple substrates including an array of xenobiotics and environmental carcinogens. 326 Lebanese women of whom 99 were cancer free (controls) and 227 were diagnosed with breast cancer (cases) were included. Blood for DNA was collected and medical charts were reviewed. Three genotyping methods were employed including: (1) restriction fragment length polymorphism (RFLP) for CYP2E1*5B, CYP2E1*6, NAT2*5 and NAT2*6; (2) gel electrophoresis for GSTM1 and GSTT1; and (3) real-time PCR for GSTP1 Ile/Val polymorphism. We analyzed the relationship between genetic susceptibilities in selected xenobiotic metabolizing genes and breast cancer risk. Allele frequencies were fairly similar to previously reported values from neighboring populations with relevant migration routes. There were no statistically significant differences in the distribution of variant carcinogen metabolizing genes between cases and controls even after adjusting for age at diagnosis, menopausal status, smoking, and alcohol intake. Despite its limitations, this is the first study that assesses the role of genetic polymorphisms in DMEs with breast cancer in a sample of Lebanese women. Further studies are needed to determine the genetic predisposition and gene-environment interactions of breast cancer in this population.

Influence of CYP2C9 and VKORC1 polymorphisms on warfarin and acenocoumarol in a sample of Lebanese people.

The authors assessed the impact of CYP2C9*2, CYP2C9*3, and/or VKORC1-1639G>A/1173C>T single-nucleotide polymorphisms on oral anticoagulants in a Lebanese population. This study recruited 231 Lebanese participants on long-term warfarin or acenocoumarol maintenance therapy with an international normalized ratio (INR) monitored at the American University of Beirut Medical Center. CYP2C9 and VKORC1 variant alleles were screened by real-time PCR. Plasma R- and S-warfarin and R- and S-acenocoumarol levels were assayed using high-performance liquid chromatography. The variant allele frequencies of CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A/1173C>T were 15.4%, 7.8%, and 52.4%, respectively. Fifty-five participants were excluded from analysis because of nontherapeutic INR values at recruitment, leaving 43 participants taking warfarin and 133 taking acenocoumarol. There was a significant decrease in the weekly maintenance dose of both drugs with CYP2C9 and VKORC1 variants when compared with wild-type patients. CYP2C9*2 had the least impact on the response to both drugs. The concentrations of R- and S-warfarin in plasma were significantly correlated with CYP2C9 genotypes. For acenocoumarol, time to reach target INR was more prolonged in patients carrying any CYP2C9 variant allele but failed to reach statistical significance because of low numbers of patients. There was no association between allelic variants and bleeding events. This is the first pharmacogenetic study of oral anticoagulants in Arabs. The authors showed that both CYP2C9 and VKORC1 polymorphisms are common in Lebanon and influence warfarin and acenocoumarol dose requirements, with the CYP2C9*2 polymorphism having less effect on acenocoumarol, the most commonly used oral anticoagulant in Lebanon.

Cytochrome P4502E1 (CYP2E1) genetic polymorphisms in a Lebanese population: frequency distribution and association with morbid diseases.

BACKGROUND: The drug-metabolizing enzyme CYP2E1 is of great interest in environmental medicine because of its involvement in the bioactivation of multiple procarcinogens. AIM: This study is aimed at determining the frequency of genetic polymorphisms of the three restriction fragment length polymorphisms: PstI and RsaI (CYP2E1*5B) and DraI (CYP2E1*6) in 216 cancer-free Lebanese individuals, as well as assessing potential association with morbid diseases in this specific population. RESULTS: The frequency of C-T allele of CYP2E*5B was 0.7% and that of A CYP2E1*6 was 6.3%. All those who carried the CYP2E1*5B allele also carried the CYP2E1*6 allele. There was a significant decrease in coronary artery disease incidence in patients carrying a CYP2E1*6 genetic polymorphism (39.7% of the noncarriers vs. 13.6% of the carriers had coronary artery disease; p = 0.019); similar results were found with the haplotype analysis (p = 0.03) but not with CYP2E1*5B alone. CONCLUSION: This is the first study on the genetic polymorphism of CYP2E1 in a Lebanese population. These data will be useful for future assessment of the role of CYP2E1 polymorphisms in the cancer population in Lebanon. It is recommended that careful population selection be performed in designing case-control studies that evaluate the association between CYP2E1 and cancer incidence. The most important factors to be controlled for are sex, body mass index, environmental exposure, lifestyle habits, and possibly, history of coronary artery disease.