Functional coupling of ATP-binding cassette transporter Abcb6 to cytochrome P450 expression and activity in liver

Hemantkumar Chavan, Feng Li, Robert Tessman, Kristen Mickey, Kenneth Dorko, Timothy Schmitt, Sean Kumer, Sumedha Gunewardena, Nilesh Gaikwad, Partha Krishnamurthy

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Although endogenous mechanisms that negatively regulate cytochrome P450 (P450) monooxygenases in response to physiological and pathophysiological signals are not well understood, they are thought to result from alterations in the level of endogenous metabolites, involved in maintaining homeostasis. Here we show that homeostatic changes in hepatic metabolite profile in Abcb6 (mitochondrial ATP-binding cassette transporter B6) deficiency results in suppression of a specific subset of hepatic P450 activity. Abcb6 null mice are more susceptible to pentobarbital-induced sleep and zoxazolamine-induced paralysis, secondary to decreased expression and activity of Cyp3a11 and Cyp2b10. The knock-out mice also show decrease in both basal and xeno-inducible expression and activity of a subset of hepatic P450s that appear to be related to changes in hepatic metabolite profile. These data, together with the observation that liver extracts from Abcb6-deficient mice suppress P450 expression in human primary hepatocytes, suggest that this mouse model may provide an opportunity to understand the physiological signals and the mechanisms involved in negative regulation of P450s.

Original languageEnglish (US)
Pages (from-to)7871-7886
Number of pages16
JournalJournal of Biological Chemistry
Volume290
Issue number12
DOIs
StatePublished - Mar 20 2015

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Chavan, H., Li, F., Tessman, R., Mickey, K., Dorko, K., Schmitt, T., Kumer, S., Gunewardena, S., Gaikwad, N., & Krishnamurthy, P. (2015). Functional coupling of ATP-binding cassette transporter Abcb6 to cytochrome P450 expression and activity in liver. Journal of Biological Chemistry, 290(12), 7871-7886. https://doi.org/10.1074/jbc.M114.605386