Cytochrome P450 2J2 plays a significant role in the epoxidation of
arachidonic acid to signaling molecules important in cardiovascular events.
CYP2J2 also contributes to drug metabolism and is responsible for the intestinal clearance of
ebastine. However, the interaction between
arachidonic acid metabolism and drug metabolism in cardiac tissue, the main expression site of
CYP2J2, has not been examined. Here we investigate an adult-derived human primary cardiac cell line as a suitable model to study metabolic drug interactions (inhibition and induction) of
CYP2J2 in cardiac tissue. The primary human cardiomyocyte cell line demonstrated similar
mRNA-expression profiles of
P450 enzymes to adult human ventricular tissue.
CYP2J2 was the dominant
isozyme with minor contributions from
CYP2D6 and
CYP2E1. Both
terfenadine and
astemizole oxidation were observed in this cell line, whereas
midazolam was not metabolized suggesting lack of
CYP3A activity. Compared with recombinant
CYP2J2,
terfenadine was hydroxylated in cardiomyocytes at a similar K(m) value of 1.5 μM. The V(max) of
terfenadine hydroxylation in recombinant
enzyme was found to be 29.4 pmol/pmol P450 per minute and in the cells 6.0 pmol/pmol P450 per minute.
CYP2J2 activity in the cell line was inhibited by
danazol,
astemizole, and
ketoconazole in submicromolar range, but also by
xenobiotics known to cause cardiac adverse effects. Of the 14 compounds tested for
CYP2J2 induction, only
rosiglitazone increased
mRNA expression, by 1.8-fold. This cell model can be a useful in vitro model to investigate the role of CYP2J2-mediated drug metabolism,
arachidonic acid metabolism, and their association to drug induced
cardiotoxicity.