CYP2J2 is the major enzyme in human liver microsomes responsible for hydroxylation of SYL-927, a novel and selective sphingosine 1-phosphate receptor 1 (S1P 1 ) agonist.

SYL-927, a novel and selective S1P1 agonist, is transferred to its active phosphate for the regulation of lymphocyte recirculation. This in vitro metabolism study is to elucidate the P450-mediated oxidation pathway of SYL-927 in human liver microsomes (HLMs). The results demonstrated that the ω-1 hydroxylated metabolite SYL-927-M was formed after incubation of SYL-927 with HLMs. Recombinant human CYP1A1 and CYP2J2 can efficiently catalyse SYL-927-M formation, followed by markedly less substrate conversion with CYP1A2, CYP2C19 and CYP2D6. Inhibition studies with chemical inhibitors and antibodies suggested that arachidonic acid, the substrate of CYP2J2, and CYP2J2-specific antibody effectively inhibited the formation of SYL-927-M in HLMs whereas no significant inhibition was observed with the inhibitors for CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, demonstrating that CYP2J2 was primarily responsible for the formation of SYL-927-M.