Role of nitric oxide in the inhibition of cytochrome P450 in the liver of mice infected with Chlamydia trachomatis.
In this study, we attempted to determine the effect of a systemic infection with Chlamydia trachomatis on cytochrome P450(CYP)-dependent metabolism in mice. Furthermore, we wanted to assess if these effects were mediated through NO. BALB/c(H-2d) female mice were inoculated intraperitoneally with the C. trachomatis mouse pneumonitis (MoPn) biovar, and induction of NO synthase (NOS) was detected by measuring [NOx] levels and inducible NOS protein content in peritoneal macrophages by Western blotting. Recovery of C. trachomatis from liver, lung, and spleen peaked at 4 days postinfection. Following cotreatment with N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, there was a significant increase in the intensity and the length of the infection. Six days after inoculation with C. trachomatis, CYP1A- and CYP2B-mediated metabolism in the liver of the mice was diminished up to 49% of control levels. However, when animals were treated with N(G)-nitro-L-arginine methyl ester at days 4 and 6 postinfection, the decrease in the metabolism of CYP1A and CYP2B was largely blocked. These results suggest that C. trachomatis infection can depress cytochrome P450 in a manner similar to other types of infections and that NO is likely to be a mediator of this depression. This finding may be of significance to patients taking drugs that are metabolized by phase I enzymes during infections with some bacteria such as C. trachomatis.
Khatsenko
O G
OG
Department of Pathology, University of California, Irvine, 92697-4800, USA.
Barteneva
N S
NS
de la Maza
L M
LM
Kikkawa
Y
Y
D000818:Animals; D002690:Chlamydia Infections / Q000097:blood / Q000201:enzymology*; D002692:Chlamydia trachomatis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000201:enzymology* / Q000382:microbiology; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019331:NG-Nitroarginine Methyl Ester