-For the purpose of a side-effect monitoring of isoniazid (INH), we investigated the relationship between the genotypes of drug-metabolizing enzymes involved in INH metabolism and the serum concentrations of INH and its metabolites in 129 tuberculosis patients hospitalizing in the National Hospital Organization Chiba-East Hospital. Genotype distributions of N-acetyltransferase 2 (NAT2), CYP2E1*5B, CYP2E1*6, Glutathione-S-transferase (GST) M1 and GST T1 were similar to those already reported in Japanese populations. Acetylating pathway of INH to acetyl isoniazid (AcINH) tended to shift to the hydrolytic pathway generating hydrazine (Hz) with the increase of mutant alleles in NAT2 gene.tration of rifampicin (RFP) than in which RFP was not detected. The effect of CYP2E1 gene polymorphisms on the serum concentration of Hz was rarely observed, while that of GST gene polymorphism was observed in intermediate acetylators of NAT2. Hz tended to accumulate in patients with GST M1 null genotype. Therefore, it is conceivable that the risk factors of Hz accumulation are as follows: NAT2 slow acetylator phenotype, high concentration of serum RFP, and GST M1 null genotype. In these cases, we think it's necessary to pay attention to the development of hepatic disorder caused by Hz.
The effects of histamine and its receptor antagonists on mouse bone marrow cells (MBMC) and MC3T3-E1 cells were studied to elucidate the precise molecular mechanisms underlying histamine activities in the respective cell types. The studied parameters were osteoclast differentiation and expressions of receptor activator of nuclear factor kappaB ligand (RANKL), histamine receptors (HR), and osteoblast differentiation markers. The osteoclastogenesis was assessed by TRAP-dye method. Expressions of RANKL, HR and the osteoblast differentiation markers were evaluated by RT-PCR analysis. In MBMC, 1 microM histamine doubled the number of osteoclast-like cells in a dose-dependent manner. Expressions of RANKL peaked at histamine concentrations of 1 microM and 0.1 microM in MBMC and MC3T3-E1, respectively. H(1)R antagonist, but not H(2)R antagonist, inhibited RANKL expressions induced by histamine in MC3T3-E1. Histamine induced expressions of cell differentiation markers in MC3T3-E1, but not in MBMC, under the conditions that RANKL expressions were induced by histamine in both types of cells. These results indicate the following: (1) Histamine induction of osteoclastogenesis is mediated by RANKL expressed via H(1)R, but not via H(2)R in mouse osteoblast-like cells; (2) and the major target of histamine action is the RANKL-RANK signaling pathway in osteocytes. This observation is consistent with the traditionally recognized histamine action of bone resorption at the osteoclast site.
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