Dataset Information

Treprostinil Improves Hepatic Cytochrome P450 Activity during Rat Liver Transplantation.

ABSTRACT:

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 6?-hydroxytestosterone, 6-hydroxychlorzoxazone, 2?- and 16?-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 TNF? and IFN? 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.

SUBMITTER: Ghonem N

PROVIDER: S-EPMC3940493 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Publications

Treprostinil Improves Hepatic Cytochrome P450 Activity during Rat Liver Transplantation.

Ghonem Nisanne N Yoshida Junichi J Murase Noriko N Strom Stephen C SC Venkataramanan Raman R

Journal of clinical and experimental hepatology 20121012 4

<h4>Background</h4>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.<h4>Methods</h4>OLT was p ...[more]

PMID: 25755454

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Project description:OBJECTIVE:Available evidence points to a role of cytochrome P450 (Cyp) drug biotransformation enzymes in central nervous system diseases, including epilepsy. Deviations in drug pharmacokinetic profiles may impact therapeutic outcomes. Here, we ask whether spontaneous recurrent seizure (SRS) activity is sufficient to modulate the expression of major Cyp enzymes in the liver and brain. METHODS:Unilateral intrahippocampal (IH) kainic acid (KA) injections were used to elicit nonconvulsive status epilepticus (SE), epileptogenesis, and SRS, as monitored by video-electroencephalography. Intraperitoneal (IP) KA injection was used to trigger generalized tonic-clonic SE. KA-injected mice and sham controls were sacrificed at 24-72 hours and 1 week post-SE (IH or IP KA), and during the chronic stage (SRS; 6 weeks post-IH KA). Liver and brain tissues were processed for histology, real-time quantitative polymerase chain reaction, Western blot, or microsomal enzymatic assay. Cyp2e1, Cyp3a13, glial fibrillary acidic protein (GFAP), IBA1, xenobiotic nuclear receptors nr1i2 (PXR), nr1i3 (CAR) and nr3c1 (glucocorticoid receptor [GR]) expression was examined. Serum samples were obtained to assay corticosterone levels, a GR activator. RESULTS:A significant increase of Cyp3a13 and Cyp2e1 transcript level and protein expression was found in the liver and hippocampi during SRS, as compared to control mice. In the ipsilateral hippocampus, Cyp2e1 and Cyp3a protein upregulation during SRS positively correlated to GFAP expression. GFAP+ , and not IBA1+ , cells colocalized with Cyp2e1 or Cyp3a expression. In the liver, a trend increase in Cyp3a microsomal activity was found during SRS as compared to control mice. The transcript levels of the Cyp upstream regulators GR, xenobiotic nr1i2, and nr1i3 receptors were unchanged at SRS. Corticosterone levels, a GR ligand, were increased in the blood post-SE. SIGNIFICANCE:SRS modifies Cyp expression in the liver and the hippocampus. Nuclear receptors or inflammatory pathways are candidate mechanisms of Cyp regulation during seizures.

Dataset Information

Treprostinil Improves Hepatic Cytochrome P450 Activity during Rat Liver Transplantation.

Background

Methods

Results

Conclusions

Publications

Treprostinil Improves Hepatic Cytochrome P450 Activity during Rat Liver Transplantation.

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