Positive Correlation between Suppressed Drug Metabolizing Enzymes and Increased iNOS Expression in Mouse Liver after Schistosoma japonicum Infection

초록

A activities of two major hepatic drug metabolizing enzymes, cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO) were examined in mice after a moderate infections of S. japonicum. Liver microsomal CYP activities determined by testosterone hydroxylation and caffeine oxidation and FMO activities by thiobenzamide S-oxidation and ranitidine N-oxidation were significantly decreased by 6 weeks but recovered in 9 weeks with significant difference between male and female. Conversely, the hepatic iNOS mRNA contents increased maximal-ly at 6-7 weeks but decreased toward normal undetectable level by 9 weeks. Immunohistochemical detection of iNOS expression sites showed initial moderate stain-ing at Kuppfer cells, intense staining of granuloma cells forming a ‘halo’ surrounding the deposited eggs (6-7 weeks) and dark focal staining only in the core of dying parasite eggs (9 weeks). Results suggested that the NO produced by iNOS and the super-oxide anion (O2-) produced by the granulomatous cells may generate the toxic peroxynitrite (ONOO-). This, in turn, may mediate the suppre-ssion of the drug metabolism by inhibiting the CYP and FMO activities in hepatocytes.