Acute mercury toxicity modulates cytochrome P450, soluble epoxide hydrolase and their associated arachidonic acid metabolites in C57Bl/6 mouse heart.

Abstract

Mercury exposure is associated with increased risk of cardiovascular disease and profound cardiotoxicity. However, the correlation between Hg(2+)-mediated toxicity and alteration in cardiac cytochrome P450s (Cyp) and their dependent arachidonic acid metabolites has never been investigated. Therefore, we investigated the effect of acute mercury toxicity on the expression of Cyp-epoxygenases and Cyp-ω-hydroxylases and their associated arachidonic acid metabolites in mice hearts. In addition, we examined the expression and activity of soluble epoxide hydrolase (sEH) as a key player in arachidonic acid metabolism pathway. Mercury toxicity was induced by a single intraperitoneal injection (IP) of 2.5 mg/kg of mercuric chloride (HgCl₂). Our results showed that mercury treatment caused a significant induction of the cardiac hypertrophy markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP); in addition to Cyp1a1, Cyp1b1, Cyp2b9, Cyp2b10, Cyp2b19, Cyp2c29, Cyp2c38, Cyp4a10, Cyp4a12, Cyp4a14, Cyp4f13, Cyp4f15, Cyp4f16 and Cyp4f18 gene expression. Moreover, Hg(2+) significantly increased sEH protein expression and activity levels in hearts of mercury-treated mice, with a consequent decrease in 14,15-, and 11,12-epoxyeicosatrienoic acids (EETs) levels. Whereas the formation of 14,15-, 11,12-, 8,9-dihydroxyeicosatrienoic acids (DHETs) was significantly increased. In conclusion, acute Hg(2+) toxicity modulates the expression of several Cyp and sEH enzymes with a consequent decrease in the cardioprotective EETs which could represent a novel mechanism by which mercury causes progressive cardiotoxicity. Furthermore, inhibiting sEH might represent a novel therapeutic approach to prevent Hg(2+)-induced hypertrophy.

• Authors: Issa E A Amara, Osama H Elshenawy, Mohamed Abdelrady, Ayman O S El-Kadi
• Journal: Toxicology letters (Toxicol Lett) Vol. 226 Issue 1 Pg. 53-62 (Apr 07 2014) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 24472606 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Biomarkers
• Isoenzymes
• RNA, Messenger
• Natriuretic Peptide, Brain
• Arachidonic Acid
• Mercuric Chloride
• 11,12-epoxy-5,8,14-eicosatrienoic acid
• 14,15-epoxy-5,8,11-eicosatrienoic acid
• Atrial Natriuretic Factor
• Cytochrome P-450 Enzyme System
• Epoxide Hydrolases
• 8,11,14-Eicosatrienoic Acid

Topics

• 8,11,14-Eicosatrienoic Acid (analogs & derivatives, metabolism)
• Animals
• Arachidonic Acid (metabolism)
• Atrial Natriuretic Factor (metabolism)
• Biomarkers (metabolism)
• Cardiomegaly (chemically induced, enzymology, genetics)
• Cytochrome P-450 Enzyme System (genetics, metabolism)
• Epoxide Hydrolases (metabolism)
• Gene Expression Regulation, Enzymologic (drug effects)
• Heart (drug effects)
• Injections, Intraperitoneal
• Isoenzymes
• Male
• Mercuric Chloride (administration & dosage, toxicity)
• Mice
• Mice, Inbred C57BL
• Myocardium (enzymology)
• Natriuretic Peptide, Brain (metabolism)
• RNA, Messenger (metabolism)