Acute arsenic toxicity alters cytochrome P450 and soluble epoxide hydrolase and their associated arachidonic acid metabolism in C57Bl/6 mouse heart.
Acute arsenic (As(III)) exposure has been reported to cause cardiac toxicity, however this toxicity was never linked to the disturbance in cytochrome P450 (P450)-mediated arachidonic acid metabolism. Therefore, we investigated the effect of acute As(III) toxicity on the expression of P450 and soluble epoxide hydrolase (sEH) and their associated arachidonic acid metabolism in mice hearts. As(III) toxicity was induced by a single intraperitoneal injection of 12.5 mg/kg of As(III). Our results showed that As(III) treatment caused a significant induction of the cardiac hypertrophic markers in addition to Cyp1b1, Cyp2b, Cyp2c, Cyp4f, and sEH gene expression in mice hearts. Furthermore, As(III) increased sEH protein expression and activity in hearts with a consequent decrease in 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) formation. Whereas the formation of 8,9-, 11,12-, 14,15-dihydroxyeicosatrienoic acids (DHETs) was significantly increased. As(III) also increased sEH mRNA and protein expression levels in addition to the hypertrophic markers which was reversed by knockdown of sEH in H9c2 cells. In conclusion, acute As(III) toxicity alters the expression of several P450s and sEH enzymes with a consequent decrease in the cardioprotective EETs which may represent a novel mechanism by which As(III) causes progressive cardiotoxicity. Furthermore, inhibiting sEH might represent a novel therapeutic approach to prevent As(III)-induced hypertrophy.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Anwar
A
Anwar-Mohamed
Ahmed A
AA
El-Sherbeni
Seok H
SH
Kim
Hassan N
HN
Althurwi
Beshay N M
BN
Zordoky
Ayman O S
AO
El-Kadi
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001151:Arsenic / Q000633:toxicity*; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology*; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D012995:Solubility; D023382:Toxicity Tests, Acute
D015415:Biomarkers; D016207:Cytokines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D020097:Natriuretic Peptide, Brain; D016718:Arachidonic Acid; D009320:Atrial Natriuretic Factor; D003577:Cytochrome P-450 Enzyme System; C092073:cardiotrophin 1; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse; D001151:Arsenic