Glutathione S-transferase M1 and T1 polymorphisms and the risk of mild hepatotoxicity induced by carbamazepine in a tunisian population study.

BACKGROUND: The aim of this study was to evaluate whether the glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) null alleles may contribute to carbamazepine-induced hepatotoxicity. METHODS: A cross-sectional prospective study was conducted to identify the frequency distribution of GSTM1 and GSTT1 alleles in 129 Tunisian epileptic patients treated with carbamazepine. Null alleles were determined using a Polymerase Chain Reaction. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by standard methods. RESULTS: Our results showed that the frequencies of GSTM1 (-) null allele and GSTT1 null (-) allele were 74.4 and 17.8% respectively. The ALT and AST levels were elevated in 46 (35.7%) and 33 (25.6%) cases. The mean values of ALT and AST were approximately 1.32 and 3.61 times higher than the upper limit of normal levels, respectively. The values of ALT and AST were significantly higher in GSTM1 (-) allele than in GSTM1 (+) (p = 10-3.and 0.004, respectively). The level of ALT was significantly higher in combination of GSTM1 (-)/T1(-) than in combined GSTM1(-)/T1(+) and combined GSTM1(+)/T1(+) (p = 0.2 and 0.03, respectively), and that of AST was significantly higher in combination of GSTM1(-)/T1(-) and in combination of GSTM1(+)/T1(-) than in combination of GSTM1(+)/T1(+) (p = 10-3 and 10-3, respectively). CONCLUSIONS: Our findings suggest that the GSTM1 (-) allele may be considered as a key factor for the development of carbamazepine-induced hepatotoxicity. Results related to GSTT (-) allele and elevation in AST levels should be considered with caution as AST may be elevated in other pathophysiological conditions.

Effects of EPHX1 and CYP3A4*22 genetic polymorphisms on carbamazepine metabolism and drug response among Tunisian epileptic patients.

The aim of this study was to evaluate the impact of polymorphisms in the EPHX1 (c.416A > G, c.337T > C) and CYP3A4*22 genes involved in carbamazepine (CBZ) metabolism and pharmacoresistance among 118 Tunisian patients with epilepsy under maintenance dose of CBZ. These genetic polymorphisms were analyzed by PCR-RFLP. Associations between plasma CBZ concentration, CBZ-E concentration, maintenance doses and metabolic ratio (CBZ-E:CBZ, CBZ-D:CBZ-E) were analyzed with each polymorphism. Both variants of EPHX1 c.416A > G and c.337T > C are significantly associated with higher metabolic ratio CBZ-E:CBZ and seem to decrease the activity of the epoxide hydrolase. The CYP3A4*22 variant allele is significantly associated with lower CBZ-D:CBZ-E ratio and seems also to be associated with less activity of the cytochrome. Our data suggest that certain polymorphisms of metabolizing enzyme genes could influence inter-individual variability of CBZ metabolism.

Fatty acid profiles in demented patients: identification of hexacosanoic acid (C26:0) as a blood lipid biomarker of dementia.

BACKGROUND: Several lipid metabolism alterations have been described in the brain and plasma of Alzheimer's disease (AD) patients, suggesting a relation between lipid metabolism alteration and dementia. OBJECTIVE: We attempted to identify blood fatty acids as biomarkers of dementia. METHODS: Fatty acid profiles were established using gas chromatography with or without mass spectrometry on matched plasma and red blood cells (RBCs) of demented patients diagnosed with AD, vascular dementia, or other dementia, and compared with a control group of elderly individuals. The severity of dementia was evaluated with the Mini-Mental State Examination test. RESULTS: Fatty acid analysis showed significant variations of fatty acid levels in demented patients including AD patients. The highest plasma and RBC accumulation was found with hexacosanoic acid (C26:0). Our data also support that alterations of desaturase and elongase activities may contribute to cognitive dysfunction. CONCLUSION: The variations of fatty acid levels and the accumulation of C26:0 in the plasma and RBCs highlight an alteration of fatty acid metabolism in demented patients and point toward possible peroxisomal dysfunction. It is suggested that C26:0 may constitute a convenient blood biomarker of dementia that could be useful in routine medical practice.

Effects of glutathione S-transferase M1 and T1 deletions on epilepsy risk among a Tunisian population.

Glutathione-S-transferases enzymes are involved in the detoxification of several endogenous and exogenous substances. In this present study, we evaluated the effects of two glutathione-S-transferase polymorphisms, (GSTM1 and GSTT1) on epilepsy risk susceptibility in a Tunisian population. These polymorphisms were analyzed in 229 healthy subjects and 98 patients with epilepsy, using a polymerase chain reaction (PCR). Odds ratio (ORs) was used for analyzing results. The study results demonstrated that individuals with the GSTM1 null genotype were at an increased risk of developing epilepsy [OR=3.80, 95% confidence interval (CI) (2.15-4.78)], whereas no significant effects were observed between individuals with GSTT1 null genotype and epilepsy risk [OR=1.15, 95% CI (0.62-2.12)]. These genotyping finding revealed that the absence of GSTM1 activity could be contributor factor for the development of epilepsy disease.

[Non-metastatic thrombosis of the superior sagittal sinus complicating Burkitt's lymphoma. A case report]. / Thrombose non tumorale du sinus longitudinal supérieur compliquant un lymphome de Burkitt. A propos d'un cas.

We report a case of non-metastatic superior sagittal sinus thrombosis complicating a Burkitt's lymphoma of the small bowel, and review similar cases of this cerebrovascular disorder associated with lymphoma.