Impaired drug metabolism in mitochondrial ATP binding cassette transporter Abcb6 knockout mice: Implication towards drug interaction and safety
Hemantkumar Chavan and Partha Krishnamurthy
University of Kansas Medical Center, Kansas City, KS 66160
The ATP binding cassette transporter ABCB6 has been primarily viewed as a protein that plays a functional role in heme synthesis. Recent studies however demonstrate that non-functional mutations in the ABCB6 gene are associated with developmental defects, growth and proliferation defects, defects in pigmentation and blood group alterations. As part of a broad effort to define the extent of functional diversity of ABCB6-regulated events in vivo, we generated Abcb6 null mice. Surprisingly, Abcb6 deficient mice displayed increased sensitivity to the anesthetic pentobarbital, which made these mice more susceptible to pentobarbital induced sleep. Further, Abcb6 knockout mice also showed altered metabolism of the classic CYP substrate zoxazolamine making these mice more susceptible to Zoxazolamine induced paralysis. Functional characterization of the Abcb6 knockout mice demonstrated unexpected alterations in the basal expression and function of a specific set of hepatic P450 isoenzymes, despite only a modest, statistically non-significant decrease, in hepatic heme levels. More interestingly, Abcb6 mediated alteration in the expression of CYP450 enzymes could not be restored to normal values with heme supplementation in Abcb6 null mice, suggesting that altered P450 function in Abcb6 deficient mice is independent of Abcb6’s role as a regulator of heme synthesis. Our observations shed light on the potential complex functions of Abcb6 in vivo and suggest that modulation of Abcb6 function in humans and animals may significantly affect metabolism of both endogenous compounds and xenobiotics.