title: Involvement of CYP2J2 on the intestinal first-pass metabolism of antihistamine drug, astemizole.
abstract: Orally administered astemizole is well absorbed but undergoes an extensive first-pass metabolism to O-desmethylastemizole. Desmethylastemizole is formed in the human microsomal systems of the small intestine as well as the liver, which suggests the role of cytochromes P450 (P450s) in the first-pass metabolism of astemizole. Human P450s involved in the O-demethylation of astemizole have, however, not been identified, and the involvement of twelve known drug-metabolizing P450s were denied. During the course of the P450 identification study, higher activities of the astemizole O-demethylation in the rabbit small intestine than in the liver (about 3-fold) were found. These data suggest the possible involvement of CYP2J, since P450 included in this subfamily is dominantly expressed in the small intestine of rabbits. Therefore, CYP2J2 cDNA has been isolated from the human cDNA library and expressed in COS-1 cells. A clear activity of astemizole O-demethylation was detected in recombinant CYP2J2 with K(m) = 0.65 microM and V(max) = 1129 pmol/nmol P450/min. Expression of the immunoreactive protein with CYP2J2 antibody was detected in the small intestine and liver. Expression levels of the immunoreactive protein with the CYP2J2 antibody in the small intestine were well correlated with the activities of the astemizole O-demethylation (r = 0.901, n = 5, p < 0.05). The CYP2J2 substrates, arachidonic acid and ebastine, strongly inhibited the microsomal astemizole O-demethylation in the human small intestines and recombinant CYP2J2. These results indicate the involvement of CYP2J2 in the presystemic elimination of astemizole in the human small intestine.
authors.affiliation: Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Tomoe
authors.initials: T
authors.lastname: Hirama
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Matsubara
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nagata
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamazoe
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D016718:Arachidonic Acid / Q000494:pharmacology; D016589:Astemizole / Q000493:pharmacokinetics*; D015153:Blotting, Western; D002090:Butyrophenones / Q000494:pharmacology; D019556:COS Cells / Q000378:metabolism; D002522:Chlorocebus aethiops; D002851:Chromatography, High Pressure Liquid; D003001:Cloning, Molecular; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D003640:Dealkylation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015723:Gene Library; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D011817:Rabbits; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D002090:Butyrophenones; C000717350:CYP2J2 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D006634:Histamine H1 Antagonists; D010880:Piperidines; D011994:Recombinant Proteins; D016718:Arachidonic Acid; D016589:Astemizole; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D000090762:Cytochrome P-450 CYP2J2; C058249:ebastine