The cytochrome P450 slow metabolizers CYP2C92 and CYP2C93 directly regulate tumorigenesis via reduced epoxyeicosatrienoic acid production

Increased expression of cytochrome P450 CYP2C9, together with elevated levels of its products epoxyeicosatrienoic acids (EET), is associated with aggressiveness in cancer. Cytochrome P450 variants CYP2C92 and CYP2C93 encode proteins with reduced enzymatic activity, and individuals carrying these variants metabolize drugs more slowly than individuals with wild-type CYP2C91, potentially affecting their response to drugs and altering their risk of disease. Although genetic differences in CYP2C9-dependent oxidation of arachidonic acid (AA) have been reported, the roles of CYP2C92 and CYP2C93 in EET biosynthesis and their relevance to disease are unknown. Here, we report that CYP2C92 and CYP2C93 metabolize AA less efficiently than CYP2C91 and that they play a role in the progression of non–small cell lung cancer (NSCLC) via impaired EET biosynthesis. When injected into mice, NSCLC cells expressing CYP2C92 and CYP2C93 produced lower levels of EETs and developed fewer, smaller, and less vascularized tumors than cells expressing CYP2C91. Moreover, endothelial cells expressing these two variants proliferated and migrated less than cells expressing CYP2C1. Purified CYP2C92 and CYP2C93 exhibited attenuated catalytic efficiency in producing EETs, primarily due to impaired reduction of these two variants by NADPH-P450 reductase. Loss-of-function SNPs within CYP2C92 and CYP2C93 were associated with improved survival in female cases of NSCLC. Thus, decreased EET biosynthesis represents a novel mechanism whereby CYPC292 and CYP2C93 exert a direct protective role in NSCLC development.