Abstract
Cytochromes P450 are a family of monooxygenase enzymes required for biosynthetic reactions in the body and for the metabolism of pharmaceutical drugs. Compared to our understanding of P450 enzymology, little is known about the post‐translational control of P450 activity. Progesterone Receptor Membrane Component 1 (PGRMC1) is a membrane‐bound hemoprotein that is highly expressed in the liver and binds >20 P450s in vivo. Dap1p/PGRMC1 binds and promotes the activity of CYP51A1 in yeast and cultured cells. To understand the function of PGRMC1 in relation to P450 biology, we generated whole‐body Pgrmc1 KO mice. Proteomic and transcriptomic data in Pgrmc1−/Y mouse livers showed that 81% of detectable P450s are downregulated at the protein level (17/21), while 83% of detectable P450s are unchanged at the transcript level (66/80). The constitutively expressed cytochrome P450 Cyp1A2, which is homologous to human CYP1A2, follows this trend. Consistent with a reduction in protein level, the Vmax of the Cyp1A2‐dependent O‐deethylation of 7‐ethoxycoumarin is 57% lower in Pgrmc1−/Y liver microsomes. In PGRMC1 KO human fibroblasts, PGRMC1 doubles the half‐life of CYP1A2 in a heme‐independent manner. These proteomic, transcriptomic, and turnover data establish PGRMC1 as a novel post‐translational stabilizer of Cyp1A2. Given that our proteomic data identified 17 P450s that are downregulated in Pgrmc1−/Y liver, these data suggest a broad role for PGRMC1 in post‐translational cytochrome P450 stability.Support or Funding InformationNIHF31HL131185 / AHA15PRE25250008 / NIHT32GM007445 / NIHRO1HL077588This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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