NAT2 and CYP2E1 polymorphisms and susceptibility to first-line anti-tuberculosis drug-induced hepatitis.

BACKGROUND: Most cases with anti-tuberculosis drug-induced hepatotoxicity (ATDH) have been attributed to isoniazid. OBJECTIVE: To evaluate whether the polymorphisms of the cytochrome P450 2EI (CYP2E1) and N-acetyltransferase 2 (NAT2) gene are associated with ATDH. DESIGN: A total of 140 tuberculosis (TB) patients without liver diseases before treatment who received anti-tuberculosis treatment were followed prospectively. Their CYP2E1 and NAT2 genotypes were determined using the TaqMan polymerase chain reaction assay. RESULTS: Forty-five (32.1%) patients were diagnosed with ATDH. No significant differences were reported in age and sex between patients with and without ATDH. Slow acetylators defined by NAT2 genotypes had a higher risk of hepatotoxicity than rapid acetylators (51.2% vs. 25.2%, P = 0.0026). Odds ratio (OR) analysis showed that slow acetylator status (OR 3.15, 95%CI 1.47-6.48) was the only independent risk factor for ATDH. Pyrazinamide co-administration induced hepatitis was also associated with NAT2 acetylator status. CYP2E1 c1/c1 homozygotes are prone to developing more severe hepatotoxicity than other c1/c2 and c2/c2 genotypes. CONCLUSION: The slow acetylator status of NAT2 is a significant susceptibility risk factor for ATDH. CYP2E1 is associated with the severity of ATDH.

Expression of wild-type alpha-catenin protein in cells with a mutant alpha-catenin gene restores both growth regulation and tumor suppressor activities.

Recent studies indicate that disruption of the E-cadherin-mediated cell-cell adhesion system is frequently associated with human cancers of epithelial origin. Reduced levels of both E-cadherin and the associated protein, alpha-catenin, have been reported in human tumors. This report describes the characterization of a human ovarian carcinoma-derived cell line (Ov2008) which expresses a novel mutant form of the alpha-catenin protein lacking the extreme N terminus of the wild-type protein. The altered form of alpha-catenin expressed in Ov2008 cells fails to bind efficiently to beta-catenin and is localized in the cytoplasm. Deletion mapping has localized the beta-catenin binding site on alpha-catenin between amino acids 46 and 149, which encompasses the same region of the protein that is deleted in the Ov2008 variant. Restoration of inducible expression of the wild-type alpha-catenin protein in these cells caused them to assume the morphology typical of an epithelial sheet and retarded their growth in vitro. Additionally, the induction of alpha-catenin expression in Ov2008 cells injected into nude mice attenuated the ability of these cells to form tumors. These observations support the classification of alpha-catenin as a growth-regulatory and candidate tumor suppressor gene.

Can pharmacokinetic dosing decrease nephrotoxicity associated with aminoglycoside therapy.

A randomized, controlled clinical trial was performed to determine whether individualized dosing by use of Bayesian pharmacokinetic modeling could decrease nephrotoxicity accosted with aminoglycoside therapy. Two hundred forty-three patients receiving aminoglycosides for suspected or proven infection were randomly assigned to one of three groups: usual physician-directed dosing (Group 1), pharmacist-assisted dosing (Group 2), or pharmacist-directed dosing (Group 3). Dosing in Groups 2 and 3 was based on a Bayesian pharmacokinetic dosing program, whereas Group 1 served as the control group. Individualized dosing resulted in higher mean postinfusion (peak) serum aminoglycoside levels, higher ratios of mean peak level to minimum inhibitory concentration (peak/MIC ratios), and a trend toward lower trough serum levels. Milligrams per dose were higher and number of doses per day was lower in the pharmacist-dosed groups. However, the incidence of nephrotoxicity (> or = 100% increase in serum creatinine) was not different among the three groups (16, 27, and 16% in Groups 1, 2, and 3, respectively). Similarly, severity of toxicity was not affected by the dosing intervention. Risk factors for toxicity included duration of therapy, shock, treatment with furosemide, older age, and liver disease. After controlling for these factors, the dosing intervention still had no effect on nephrotoxicity. It was concluded that Bayesian pharmacokinetic dosing did not decrease the risk of nephrotoxicity associated with aminoglycoside therapy.