Inhibition of nitric oxide synthesis improves detoxication in inflammatory liver dysfunction in vivo.
Inflammatory stimulation of the liver induces nitric oxide (NO) biosynthesis and suppression of detoxication. In this study the effect of NO biosynthesis on cytochrome P-450 (CYP) enzyme activity was investigated by comparing in vivo and in vitro assays. To establish liver inflammation, CD rats were injected with Corynebacterium parvum (C. parvum) suspension. After 5 days NO biosynthesis was highly induced as indicated by increased NO2- plus NO3- serum concentrations. At the same time the aminopyrine breath test (ABT), measuring CYP activity in vivo, was reduced to 42% and the in vitro assay of aminopyrine turnover was suppressed to 12% of NaCl- injected controls. When C. parvum-injected animals were treated with the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA), CYP activities significantly improved with an ABT of 76% and an in vitro aminopyrine turnover of 47% of controls. Neither C. parvum injections nor L-NMMA treatment resulted in a significant change of CYP protein concentrations. These data indicate that suppression of xenobiotic metabolism can be attenuated by inhibition of NO biosynthesis during an ongoing process of inflammation.
Veihelmann
A
A
Department of Surgery, Technische Universität München, Germany.
Brill
T
T
Blobner
M
M
Scheller
I
I
Mayer
B
B
Prölls
M
M
Himpel
S
S
Stadler
J
J
D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016908:Gram-Positive Bacterial Infections; D006520:Hepatitis, Animal / Q000378:metabolism* / Q000382:microbiology / Q000503:physiopathology*; D008658:Inactivation, Metabolic; D008099:Liver / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009994:Osmolar Concentration; D011425:Propionibacterium acnes; D051381:Rats; D011919:Rats, Inbred Strains; D019323:omega-N-Methylarginine / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019388:Cytochrome P-450 CYP1A2