Altered Protein Expression of Cardiac CYP2J and Hepatic CYP2C, CYP4A, and CYP4F in a Mouse Model of Type II Diabetes—A Link in the Onset and Development of Cardiovascular Disease?

Abstract

Arachidonic acid can be metabolized by cytochrome P450 (CYP450) enzymes in a tissue- and cell-specific manner to generate vasoactive products such as epoxyeicosatrienoic acids (EETs-cardioprotective) and hydroxyeicosatetraenoic acids (HETEs-cardiotoxic). Type II diabetes is a well-recognized risk factor for developing cardiovascular disease. A mouse model of Type II diabetes (C57BLKS/J-db/db) was used. After sacrifice, livers and hearts were collected, washed, and snap frozen. Total proteins were extracted. Western blots were performed to assess cardiac CYP2J and hepatic CYP2C, CYP4A, and CYP4F protein expression, respectively. Significant decreases in relative protein expression of cardiac CYP2J and hepatic CYP2C were observed in Type II diabetes animals compared to controls (CYP2J: 0.80 ± 0.03 vs. 1.05 ± 0.06, n = 20, p < 0.001); (CYP2C: 1.56 ± 0.17 vs. 2.21 ± 0.19, n = 19, p < 0.01). In contrast, significant increases in relative protein expression of both hepatic CYP4A and CYP4F were noted in Type II diabetes mice compared to controls (CYP4A: 1.06 ± 0.09 vs. 0.18 ± 0.01, n = 19, p < 0.001); (CYP4F: 2.53 ± 0.22 vs. 1.10 ± 0.07, n = 19, p < 0.001). These alterations induced by Type II diabetes in the endogenous pathway (CYP450) of arachidonic acid metabolism may increase the risk for cardiovascular disease by disrupting the fine equilibrium between cardioprotective (CYP2J/CYP2C-generated) and cardiotoxic (CYP4A/CYP4F-generated) metabolites of arachidonic acid.

Imbalance of Drug Transporter-CYP450s Interplay by Diabetes and Its Clinical Significance

“…A report showed that protein expression and activity of hepatic CYP2E1 in STZ-induced diabetic rats were increased by three-and 2.5-fold in comparison to control rats, respectively. The increases were in line with the increased oxidative stress, demonstrating crucial roles of CYP2E1 in stress-induced pathological processes under diabetic status [31,32,36].…”

“…Growing evidence has demonstrated that diabetes increases the expression of some CYP450s (such as CYP2A1, CYP1A2, CYP2B1/2, CYP2C6, CYP2C7, CYP3A1/2 and CYP2E1) in rats [9,11,12,[26][27][28][29][30], although opposite reports have also been shown [31,32]. The induction of CYP3A1/2 led to lower plasma exposure of simvastatin [12], atorvastatin [9,11], verapamil [27,29] and lidocaine [30] following intravenous dose to diabetic rats.…”

Molecular Functionality of Cytochrome P450 4 (CYP4) Genetic Polymorphisms and Their Clinical Implications

“…Seven CYP4F isoforms, CYP4F2, CYP4F3A, CYP4F3B, CYP4F8, CYP4F11, CYP4F12 , and CYP4F22 , are clustered on chromosome 19 and are encoded by six genes. CYP4A isoforms include CYP4A11 and CYP4A22 on chromosome 1 [3], and the remaining CYP4 subfamily genes are CYP4B1 , CYP4V2 , CYP4X1 , and CYP4Z1 [4]. The major sites of CYP4A11 expression are the liver and kidney [5].…”

“…Cytochrome P450s (CYPs) are a superfamily of enzymes located either in the inner membrane of mitochondria or in the endoplasmic reticulum membrane of eukaryotic cells. There are 57 CYP proteins encoded in the human genome, which are responsible for the metabolism of numerous endogenous and exogenous compounds [1,2,3]. CYPs mainly oxidize these compounds to generate more hydrophilic metabolites, enhancing their excretion outside the body and thus playing a major role in the detoxification of toxic chemicals [1].…”

Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape—A Summary of This Indispensable Special Issue

“…Lakowski and colleagues from University of Manitoba and Alberta identified the metabolism, excretion, antioxidant, anti-inflammatory, and anticancer properties of curcuminoids and determined disposition in rodents [ 7 , 8 ]. Simard and colleagues from Université Laval set out to determine if altered protein expression of cardiac and hepatic drug metabolizing enzymes in a mouse model of Type II diabetes lead to the onset and development of cardiovascular disease [ 9 ]. Leung, Turgeon, and Michaud from the Université de Montréal presented a study of statin- and loratadine-induced muscle pain mechanisms using human skeletal muscle cells [ 10 ].…”