Alteration of drug biotransformation and elimination during infection and inflammation

Renton, Kenneth W.

doi:10.1016/s0163-7258(01)00165-6

Cited by 184 publications

(161 citation statements)

References 155 publications

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“…25 The inflammatory responses and cytokines generated during liver regeneration are known to downregulate CYP. 26 However, it is not clear to what extent each individual cytokine contributes to the overall reduced expression of the various CYP isozymes. Recent studies have found that several different liver-enriched transcription factors including HNF-1, HNF-3, HNF-4, and C/EBP β, and the more ubiquitously expressed factors Sp1, GABP β, and NF2d9 are responsible for governing the transcription of P450 genes.…”

Section: Resultsmentioning

confidence: 99%

Gene Expression Profile at the G1/S Transition of Liver Regeneration after Partial Hepatectomy in Mice

et al. 2004

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Liver is a quiescent organ with >90% of the cells present in the G 0 stage of the cell cycle. However, adult hepatocytes have enormous ability to proliferate in response to liver injury. After 70% liver resection hepatocytes enter the cell cycle in a highly synchronized manner and undergo 1 to 2 rounds of cell division to restore the lost organ mass, thus, representing one of the most reliable model systems to study cell cycle progression in vivo. Using high density oligonucleotide micro-array we analyzed the expression patterns of genes at the G 1 /S transition of liver regeneration in comparison to quiescent livers. The G 1 /S boundary was identified by in vivo BrdU pulse labeling and we observed 199 genes/ESTs which were either up/down regulated at this time point. These differentially regulated genes have a wide range of functions including transcriptional regulation, signal transduction, cell cycle regulation, chromatin reorganization, protein targeting, metabolism, transport, surface receptors, circadian rhythms, xenobiotic metabolism, inflammation and acute phase response. The functions of most of the genes identified in this screen are not known in the process of liver regeneration and cell cycle control at G 1 /S transition.

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Section: Resultsmentioning

confidence: 99%

Gene Expression Profile at the G1/S Transition of Liver Regeneration after Partial Hepatectomy in Mice

et al. 2004

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“…Infections and inflammatory stimuli cause a reduction of drug elimination and metabolism of other xenobiotics (Morgan, 1997;Renton, 2001). The major part of the reduction is believed to be consequence of decreased cytochrome P450 (P450) enzyme levels and activities in liver.…”

mentioning

confidence: 99%

Mechanisms of Down-Regulation of CYP2E1 Expression by Inflammatory Cytokines in Rat Hepatoma Cells

Hakkola

Hu²,

Ingelman‐Sundberg³

2003

J Pharmacol Exp Ther

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CYP2E1 is one of the major cytochrome P450 forms whose expression is strongly inhibited by inflammatory cytokines in humans and rodents. In the present study, we have used the Fao rat hepatoma cell line that constitutively expresses CYP2E1 enzyme to investigate mechanisms of cytokine action. The cells were treated with interleukin (IL)-1␤, tumor necrosis factor-␣ (TNF␣), or IL-6 for 24 or 72 h, and the expression of CYP2E1 was monitored at the transcriptional, mRNA, and protein levels. All three cytokines decreased the CYP2E1 mRNA levels after 24 h, and the effect was even stronger after 72 h. In contrast, significant inhibition of CYP2E1 protein was seen only after 72 h. In transfection assays using a CYP2E1 5Ј Ϫ3685 to ϩ29-luciferase construct, it was found that IL-6 inhibited gene transcription after 24 h, but a similar effect by IL-1␤ and TNF␣ was registered only after 72 h. Using 5Ј deletions of the CYP2E1 5Ј-reporter construct a responsive region for the IL-6 effect was located to Ϫ669 to Ϫ507 base pairs in the CYP2E1 5Ј-flanking region. Interestingly, IL-1␤, but not TNF␣, was found to reduce hepatocyte nuclear factor (HNF)-1␣ binding to the CYP2E1 promotor. However, the transactivation function of HNF-1␣ was found to be impaired in Fao cells. In mouse primary hepatocytes, IL-1␤ decreased HNF-1␣-mediated transactivation. In conclusion, our data indicate that inflammatory cytokines inhibit CYP2E1 expression by multiple mechanisms, including control of HNF-1␣ function and regulation of other transcriptional factors acting on the CYP2E1 5Ј-upstream regulatory region. In addition, regulation of factors of importance for the CYP2E1 mRNA stability may be involved.

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“…Several studies have investigated whether the activity of hepatic CYP450 enzymes in experimental models of liver inflammation or infection are down-regulated, which can cause dose-dependent drug toxicity associated with impaired drug clearance in vivo. 19,20 Yet, data that directly examines effects of cold I/R injury on CYP450 activity during OLT has not been obtained. Knowing the extent of cold I/R-induced injury on hepatic CYP450 activity prior to liver transplantation can serve as a guide in proper drug therapy, especially in the early post-operative period, and increase the number of available organs for transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have demonstrated that the activities of many hepatic CYP450 enzymes in experimental models of liver inflammation or infection and in man are down-regulated, which can cause dosedependent drug toxicity associated with impaired in vivo drug clearance. 19,20 In most cases, the decreased activity is accompanied or preceded by decreased hepatic levels of the corresponding CYP450 mRNA and protein expression. 6 Although, the different models of inflammation can result in different rates of drug clearance and or reduced microsomal metabolism of drugs.…”

Section: Discussionmentioning

confidence: 99%

Treprostinil Improves Hepatic Cytochrome P450 Activity during Rat Liver Transplantation

Ghonem

Yoshida²,

Murase³

et al. 2012

Journal of Clinical and Experimental Hepatology

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Background: Cytochrome P450 (CYP450) activity is an important indicator of liver graft function. CYP450 activity is altered by pro-inflammatory cytokines, which are associated with ischemia-reperfusion (I/R) injury during orthotopic liver transplantation (OLT). Treprostinil, an FDA-approved prostacyclin analog, ameliorated cold I/R injury during rat OLT. We hypothesized that treprostinil would improve CYP450 activity in liver graft during cold I/R injury post-OLT. Methods: OLT was performed in syngeneic male Lewis rats with 18 h graft preservation in cold UW solution. Donor and recipients received treprostinil (100 ng/kg/min) or matching placebo for 24 h before and up to 48 h post-OLT. Liver graft mRNA and protein expression of CYP450 isoforms were analyzed by qRT-PCR and Western blot analysis, respectively. The formation rates of 1-hydroxymidazolam and 6b-hydroxytestosterone, 6-hydroxychlorzoxazone, 2a-and 16a-hydroxytestosterone in liver graft microsomes served as markers for CYP3A, CYP2E1, and CYP2C11 activity, respectively, and were measured by LC-MS. Results: Treprostinil significantly decreased serum ALT and AST levels at 6-48 h after OLT, compared to placebo. The expressions of TNFa and IFNg mRNA in the liver graft were significantly inhibited in the treprostinil-treated group at 1 h post-reperfusion. Treprostinil restored CYP2E1 protein expression to that of normal liver and significantly improved CYP3A activity to more than two-fold of placebo early post-OLT. Conclusions: Treprostinil significantly ameliorated hepatic injury, reduced expression of pro-inflammatory cytokines, and improved CYP450 activity in liver graft early post-OLT. These findings suggest that treprostinil has the potential to serve as a therapeutic option to protect liver graft function against I/R injury during clinical OLT. ( J CLIN EXP HEPATOL 2012;2:323-332)

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Alteration of drug biotransformation and elimination during infection and inflammation

Cited by 184 publications

References 155 publications

Gene Expression Profile at the G1/S Transition of Liver Regeneration after Partial Hepatectomy in Mice

Gene Expression Profile at the G1/S Transition of Liver Regeneration after Partial Hepatectomy in Mice

Mechanisms of Down-Regulation of CYP2E1 Expression by Inflammatory Cytokines in Rat Hepatoma Cells

Treprostinil Improves Hepatic Cytochrome P450 Activity during Rat Liver Transplantation

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