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

초록

Aactivities 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.