약물대사에서 NO에 의한 FMO 효소 활성도 억제

초록

Together with the heme containing cytochrome P-450 monooxygenases (CYPs), the flavin-containing monooxygenase (FMO) contained in liver microsomes catalyzed the oxidation of many clinical medicines and plant alkaloids. However, the animals with sepsis upon infection by virus, bacteria, fungus and parasites, the hepatic drug metabolism is generally known to be suppressed. Under such septic condition, NO is produced in great abundance due to induction of iNOS in hepatocytes. Thus, in the present study, the effect of NO on the CYP and FMO has been examined by inducing the hepatic NO production upon prior induction of iNOS with intraperitoneal injection of bacterial lipopolysaccharide (LPS) in rats. At 24 hr after the LPS injection, the hepatic microsomal FMO activity as well as the level of hepatic FMO1 mRNA were decreased. The iNOS mRNA content, however, was increased more than 2 fold. The hepatic microsomal FMO activity has been determined either by the S-oxidation or the NADPH oxidation rates using the substrates like thiobenzamide (TB), trimethylamine (TMA), N,N-dimethylaniline (DMA0 and imipramine (IMP). The FMO activities measured even after removing the participation of CYPs in the oxidation of these drugs by prior buddling with CO were also decreased. When the endogenous production of NO in the LPS treated (iNOS induced) rats was inhibited by co-infection of NG-nitro-L-arginine (L-NNA), a well known competetive inhibitor of L-arginine, the FMO1 mRNA level was restored. Futhermore, the FMO activities determined with hepatic microsomes isolated from the L-NNA treated rats were also partially or completely restored to the control levels. However, the FMO activities obtained with normal rat liver microsomes were not deceased after adding the sodium nitrooprusside (SNP), a well known NO donor. Combined all together, these results indicate that the reduction of FMO activity produced by prior injection of LPS (induction of iNOS) is produced by the transcriptional suppr