Inter-ethnic differences in genetic polymorphisms of xenobiotic-metabolizing enzymes (CYP1A1, CYP2D6, NAT1 and NAT2) in healthy populations: correlation with the functional in silico prediction

Several studies have shown that many polymorphisms of the xenobiotic-metabolizing enzymes (XME) affect either enzymatic functions or are associated with various aspects of human health. Owing to the presence of these single nucleotide variants (SNVs), differences in detoxification capacity have been observed between many ethnicities. The aim of this investigation was to study the prevalence of four polymorphisms in XME among various ethnic groups. Attention was focused on polymorphisms of CYP2D6 (rs1058172, G>A, p.Arg365His), CYP1A1 (rs4646421, c.-26-728C>T), NAT1 (rs4921880, c.-85-1014T>A) and NAT2 (rs1208, A>G, p.Arg268Lys). These polymorphisms were analyzed in 261 healthy Tunisians individuals in comparison with different ethnic backgrounds from hapmap database. In addition, in silico functional prediction was also performed to determine the loss of function variants. Our results demonstrated that population’s origins widely affect the genetic variability of XME enzymes and Tunisians show a characteristic pattern. In silico predictions showed a deleterious effect for p.Arg268Lys substitution on CYP2D6 function, findings confirmed its key role played in cancer susceptibility. These data show that detoxification genes structures depend on the studied population. This suggests that ethnic differences impact on disease risk or response to drugs and therefore should be taken into consideration in genetic association studies focusing on XME enzymes. Our results provide the first report on these SNV in Tunisian population and could be useful for further epidemiological investigations including targeted therapy.     

Association of CYP1A1 and CYP2D6 gene polymorphisms with head and neck cancer in Tunisian patients

The purpose of this study was to investigate the relationship between head and neck cancer (HNC) and environmental agents and polymorphisms in CYP1A1, CYP2D6, NAT1 and NAT2 metabolic enzymes genes. To the best of our knowledge, this is the first report on polymorphisms in CYP1A1 6310C>T, CYP2D6 Arg365His, NAT1 52936A>T and NAT2 Arg268Lys (NAT2*12A) genes and susceptibility to HNC in Tunisian population. We study the prevalence of these polymorphisms in 169 patients with HNC and 261 control subjects using polymerase chain reaction based methods in a Tunisian population. We detected an association between HNC and CYP1A1 6310C>T (TT) and CYP2D6 Arg365His (His/His) variant carriers (OR 1.75, P = 0.008 and OR 1.66, P = 0.016, respectively). No association was found between the polymorphisms genotypes of NAT1 52936T>A and NAT2 Arg268Lys and risk of HNC. An association between HNC and CYP1A1 (TT) genotype was found among patients with smoking (P = 0.011) and drinking habit (P = 0.009). The combinations of NAT1 (AT or AA) and NAT2 (AA) at-risk genotypes increased HNC risk (OR 4.23, P = 0.005 and OR 3.60, P = 0.048, respectively). However, the combinations of CYP1A1 (AA) and CYP2D6 (CC) genotypes decreased risk of HNC (OR 0.20; P = 0.006). Genetic polymorphisms in CYP1A1 and CYP2D6 may significantly associate with HNC in the Tunisian population. The results of this study suggest a possible gene–environment interaction for certain carcinogen metabolizing enzymes, but larger studies that fully evaluate the interaction are needed.     

Pre-existing diabetes mellitus and adverse pregnancy outcomes

ABSTRACT: BACKGROUND: Pregnancies complicated by pre-existing diabetes mellitus (PDM) are associated with a high rate of adverse outcomes, including an increased miscarriage rate, preterm delivery, preeclampsia, perinatal mortality and congenital malformations; compared to the background population. The objectives of this study are to determine the prevalence of PDM and to investigate the maternal and the neonatal outcomes of women with PDM. METHODS: This is a retrospective cohort study for women who delivered in King Khalid University Hospital (KKUH) during the period of January 1st to the 31st of December 2008. The pregnancy outcomes of the women with PDM were compared to the outcomes of all non-diabetic women who delivered during the same study period. RESULTS: A total of 3157 deliveries met the inclusion criteria. Out of the study population 116 (3.7%) women had PDM. There were 66 (57%) women with T1DM and 50 (43%) women with T2DM. Compared to non-diabetic women those with PGMD were significantly older, of higher parity, and they had more previous miscarriages. Women with PDM were more likely to be delivered by emergency cesarean section (C/S), OR 2.67, 95% confidence intervals (CI) (1.63-4.32), P < 0.001, or elective C/S, OR 6.73, 95% CI (3.99-11.31), P < 0.001. The neonates of the mothers with PDM were significantly heavier, P < 0.001; and more frequently macrosomic; OR 3.97, 95% CI (2.03-7.65), P = 0.002. They more frequently have APGAR scores <7 in 5 minutes, OR 2.61, 95% CI (0.89-7.05), P 0.057 and more likely to be delivered at <37 gestation weeks, OR 2.24, 95% CI (1.37- 3.67), P 0.003. The stillbirth rate was 2.6 times more among the women with PDM group; however the difference did not reach statistical significance, P 0.084. CONCLUSION: PDM is associated with increased risk for C/S delivery, macrosomia, stillbirth, preterm delivery and low APGAR scores at 5 min.     

Association of GSTM1 and GSTT1 Polymorphisms with Chronic Obstructive Pulmonary Disease in a Tunisian Population

GSTM1 and GSTT1 polymorphisms have been proposed in relationship with chronic obstructive pulmonary disease (COPD). We investigated the association between these polymorphisms and COPD (as well as its subtypes emphysema and chronic bronchitis) in 234 COPD patients and 182 healthy controls in the Tunisian population. Genotyping was performed using multiplex PCR. GSTM1-null genotype frequency was significantly higher in COPD patients than in controls (P = 0.02); however, multivariate analysis of cofounding variables showed no independent association with this genotype (P = 0.073). In contrast, the association of the GSTM1-null genotype with emphysema was significant, even after adjustment for risk factors (P = 0.011). There were no significant differences in GSTT1 genotypes between patients and controls. The GSTM1 null allele is likely not an independent risk factor for COPD but is related to emphysema, whereas the GSTT1 gene is not associated with the disease.     

Evaluation of Efficiency of Modified Polypropylenimine (PPI) with Alkyl Chains as Non-viral Vectors Used in Co-delivery of Doxorubicin and TRAIL Plasmid

In this study, co-delivery system was achieved via plasmid encoding TNF related apoptosis inducing ligand (pTRAIL) and doxorubicin (DOX) using carrier based on polypropylenimine (PPI) modified with 10-bromodecanoic acid. Incorporation of alkylcarboxylate chain to PPIs (G4 and G5) could improve transfection efficiency via overcoming the plasma membrane barrier of the cells and decrease cytotoxicity of PPI. Characterization of fabricated NPs revealed that PPI G5 in which 30% of primary amines were substituted by alkyl carboxylate chain (PPI G5-Alkyl 30%) has higher drug loading as compared to the other formulations. PPI G5-Alkyl 30% indicated a decreased drug release may be due to alkyl chains on the surface of PPI, which serve as an additional hindrance for drug diffusion. In vitro cytotoxicity experiments demonstrated that co-delivery system induced apoptosis of tumor cells more efficiently than each of delivery system alone. Furthermore, these results revealed that our combined delivery platform of pTRAIL and DOX using Alkyl-modified PPI G5 can significantly improve the anti-tumor activity and this strategy might develop a new therapeutic window for cancer treatment.     

Production of biosurfactant on crude date syrup under saline conditions by entrapped cells of Natrialba sp. strain E21, an extremely halophilic bacterium isolated from a solar saltern (Ain Salah, Algeria)

A bacterial strain E21 was isolated from a sample of water collected in the salt lake located close to Ain Salah, Algeria. The analysis of 16S rRNA gene sequence had indicated that the strain had 93 % sequence similarity with the genus Natrialba sp. strain E21 (GenBank, FR750525.1) and was considered extremely halophilic. Production of biosurfactant by the strain E21 with free and entrapped cells was investigated using soluble starch in the saline conditions. Biosurfactant synthesis was followed by measuring the surface tension and emulsifying index 9 days under optimal conditions (40 °C, pH 7). Some diffusional limitations in alginate and agar beads affected the kinetics of biosurfactant production when compared to that obtained with free cells culture. The minimum values of surface tension were 27 and 30 mN m^?1 achieved after 9 days with free and immobilized cells, respectively, while the corresponding maximum E24 values were 65.3 and 62.3 %, respectively. The re-use of bacterial cells along with the limited cell losses provided by the immobilized system might lead to significant reduction of the biosurfactant production cost.