Interaction of Abcb6 with Cytochrome P450s

Abstract

Modification of the enzymatic activity of cytochrome P450 (CYP450) enzymes can alter the metabolism of the drug substrate for that enzyme, and thereby alter the biological activity of the drug leading to potentially harmful drug‐drug interactions. The activity and in some cases the induction of these CYP450 family members is mediated by haem, an essential prosthetic group of these detoxifying enzymes. In the present study we investigated whether the mitochondrial half transporter Abcb6, which regulates cellular haem biosynthesis and cellular haemoprotein pool, plays a role in the expression and/or function of CYP450s. We found that over‐expression of Abcb6 in HepG2 cells lead to an increase in CYP3A4 mRNA expression. In contrast over‐expression of Abcb6 in K562 cells resulted in decreased expression of CYP3A4, CYP2E1 and CYP2D6 mRNA. We tested whether prototypical inducers of CYP450 expression regulated Abcb6 expression and found that both pregnenolone‐16α carbonitrile (PCN) and 1,4‐bis[2‐(3,5‐dichloropyridyloxy) benzene (TCPOBOP), two well known inducers of CYP450, also induced Abcb6 expression both in vitro and in vivo. Cumulatively these findings suggest that Abcb6 might play a role in the metabolism and disposition of drugs and environmental chemicals, and may affect drug clearance and drug toxicity.