Suppression of hepatic cytochrome p450-mediated drug metabolism during the late stage of sepsis in rats.
The effects of polymicrobial sepsis on the activity and gene expression of hepatic microsomal cytochrome P450 (CYP) were examined. Rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). Liver and blood samples were taken 2, 6, and 24 h after CLP. The serum aminotransferase levels and lipid peroxidation increased 24 h after CLP. The hepatic concentrations of reduced glutathione and total CYP content decreased 24 h after CLP. The CYP1A1 activity and its protein level decreased 24 h after CLP. The CYP1A2 activity decreased 2 h and 24 h after CLP. Although the CYP2B1 mRNA expression level decreased 6 h and 24 h after CLP, the CYP2B1 activity and its protein level did not change in any of the experimental groups. The CYP2E1 activity and its protein level decreased 24 h after CLP. The CYP2E1 mRNA levels were lower at both 6 h and 24 h after CLP. The TNF-alpha mRNA expression level increased 2, 6, and 24 h after CLP. The iNOS mRNA expression level increased 24 h after CLP. These findings suggest that sepsis causes abnormalities in the microsomal drug-metabolizing function, particularly in the late stage, which is associated with higher level of oxidant stress and lipid peroxidation.
Lee
Sang-Ho
SH
College of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu Suwon-si, Gyeonggi-do 440-746, South Korea.
Lee
Sun-Mee
SM
D000818:Animals; D015153:Blotting, Western; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D017931:DNA Primers / Q000737:chemistry; D005978:Glutathione / Q000378:metabolism; D007249:Inflammation; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism*; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000188:drug therapy* / Q000473:pathology*; D013997:Time Factors; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D017931:DNA Primers; D020033:Protein Isoforms; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D000637:Transaminases; D005978:Glutathione