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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
Author(s) -
Yang Shu,
Hu Jinping,
Li Yan,
Zhao Zhigang
Publication year - 2018
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2161
Subject(s) - cyp1a2 , chemistry , microsome , biochemistry , enzyme , metabolite , cyp2c8 , hydroxylation , cytochrome p450 , cyp3a4
SYL‐927, a novel and selective S1P 1 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.