The polymorphic P450 (CYP) enzyme superfamily is the most important system involved in the biotransformation of many endogenous and exogenous substances including drugs, toxins, and carcinogens. Genotyping for CYP polymorphisms provides important genetic information that help to understand the effects of xenobiotics on human body. For drug metabolism, the most important polymorphisms are those of the genes coding for CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, which can result in therapeutic failure or severe adverse reactions. Genes coding for CYP1A1, CYP1A2, CYP1B1, and CYP2E1 are among the most responsible for the biotransformation of chemicals, especially for the metabolic activation of pre-carcinogens. There is evidence of association between gene polymorphism and cancer susceptibility. Pathways of carcinogen metabolism are complex, and are mediated by activities of multiple genes, while single genes have a limited impact on cancer risk. Multigenic approach in addition to environmental determinants in large sample studies is crucial for a reliable evaluation of any moderate gene effect. This article brings a review of current knowledge on the relations between the polymorphisms of some CYPs and drug activity/toxicity and cancer risk.

2 AbstractPurpose: To evaluate the role of cytochrome 450 2D6 (CYP2D6) and ABCB1 variants on plasma risperidone concentrations and treatment response in 83 drug naive patients with first episode of psychosis.Methods: All patients were treated with risperidone for 8 weeks. The CYP2D6 genotyping was performed by allele-specific PCR-RFLP (for *3,*4,*6) and long PCR (for duplications and *5), while real-time PCR method was used for ABCB1 G2677T/A and C3435T. Plasma concentrations of risperidone and 9-OH risperidone were measured by high-preformance liquid chromatography.Results: The number of patients with the CYP2D6 wild type (wt/wt), wt/mutation (mut) and mut/mut genotype was 43, 32 and 8, respectively. The number of patients with the ABCB1 2677G/G , G/T, T/T variants was 29, 42 and 12, respectively; those with the 3435C/C, C/T and T/T was 25, 37 and 21, respectively. The CYP2D6 genotype has strong effect on steady-state dose-corrected plasma levels of risperidone, its 9-OH metabolite and active moiety, while ABCB1 2677T/T and 3435T/T genotypes hold similarly strong effects on active moiety C/D. The CYP2D6 poor metabolizers had significantly higher levels of risperidone C/D and active moiety C/D, and lower levels of 9-OH risperidone C/D. The ABCB1 3435T allele and the ABCB1 2667T-3435T haplotype carriers were more frequent among subjects without extrapyramidal syndrome. Patients showed significant improvements in positive and general symptoms, but not in negative symptoms. These changes were not related to variations in genetic and drug concentration data.Conclusion: Our findings suggest that CYP2D6 and ABCB1 G2677T and C3435T might be useful determinants of risperidone plasma concentrations, but the clinical implications of these associations in relation to treatment response and side-effects remains unclear.

Autonomic (primarily sympathetic) dysfunction is present in a large proportion of early MS patients and it seems to be related to brainstem involvement.

The sulfate anion transporter (sat-1, Slc26a1) has been cloned from rat liver, functionally characterized, and localized to the sinusoidal membrane in hepatocytes and basolateral membrane (BLM) in proximal tubules (PT). Here, we confirm previously described localization of sat-1 protein in rat liver and kidneys and report on gender differences (GD) in its expression by immunochemical, transport, and excretion studies in rats. The ∼85-kDa sat-1 protein was localized to the sinusoidal membrane in hepatocytes and BLM in renal cortical PT, with the maledominant expression. However, the real-time reversetranscription polymerase chain reaction data indicated no GD at the level of sat-1 mRNA. In agreement with the protein data, isolated membranes from both organs exhibited the male-dominant exchange of radiolabeled sulfate for oxalate, whereas higher oxalate in plasma and 24-h urine indicated higher oxalate production and excretion in male rats. Furthermore, the expression of liver, but not renal, sat-1 protein was: unaffected by castration, upregulated by ovariectomy, and downregulated by estrogen or progesterone treatment in males. Therefore, GD (males > females) in the expression of sat-1 protein in rat liver (and, possibly, kidneys) are caused by the female sexhormone-driven inhibition at the posttranscriptional level. The male-dominant abundance of sat-1 protein in liver may conform to elevated uptake of sulfate and extrusion of oxalate, causing higher plasma oxalate in males. Oxalate is then excreted by the kidneys via the basolateral sat-1 (males > females) and the apical CFEX (Slc26a6; GD unknown) in PT and eliminated in the urine (males > females), where it may contribute to the male-prevailing development of oxalate urolithiasis.

ABCB1 C1236T, G2677T/A, C3435T polymorphisms have an influence on lamotrigine serum concentrations.