PGRMC1 functions to stabilize cytochromes P450

Progesterone receptor membrane component 1 (PGRMC1) is a membrane-bound hemoprotein with many ascribed functions that binds cytochromes P450 in yeast and human cells. We generated a whole-body Pgrmc1 KO mouse to study the role of PGRMC1 in cytochrome P450 biology. Here, we show that Pgrmc1 binds at least 13 cytochromes P450 in liver, and this binding is independent of Pgrmc1 heme binding. Proteomic and transcriptomic data from Pgrmc1 KO liver show that cytochrome P450 protein levels are less abundant in the KO, and this decrease is not due to differences in transcript level. In human fibroblasts, PGRMC1 doubles the half-life of CYP1A2 in a heme-independent manner. Consistent with a reduction in protein level, the Vmax of the Cyp1A2-dependent O-deethylation of 7-ethoxycoumarin is 42% lower in Pgrmc1 KO liver membrane fraction. Cyp2e1 protein levels are 20% lower in Pgrmc1 KO liver. The Pgrmc1 KO mice are protected against Cyp2e1-mediated liver injury during acetaminophen overdose, a leading cause of acute liver failure, making PGRMC1 a clinically relevant effector of cytochrome P450 activity. Unlike binding to cytochromes P450, Pgrmc1 binds to ferrochelatase in a heme-dependent manner and does not affect ferrochelatase protein stability, suggesting that Pgrmc1 has two distinct functions in the liver. Collectively, these proteomic, transcriptomic, protein turnover, and activity data establish PGRMC1 as a novel post-translational stabilizer of cytochromes P450