title: 2,5-Dihydroxy-4-methoxybenzophenone: a novel major in vitro metabolite of benzophenone-3 formed by rat and human liver microsomes.
abstract: 1. When benzophenone-3 (2-hydroxy-4-methoxybenzophenone; BP-3) was incubated with liver microsomes of untreated rats in the presence of NADPH, the 5-hydroxylated metabolite, 2,5-dihydroxy-4-methoxybenzophenone (5-OH-BP-3), was formed as a major novel metabolite of BP-3. The 4-desmethylated metabolite, 2,4-dihydroxybenzophenone (2,4-diOH-BP), previously reported as the major in vivo metabolite of BP-3, was also detected. However, the amount of 5-OH-BP-3 formed in vitro was about the same as that of 2,4-diOH-BP. 2. The oxidase activity affording 5-OH-BP-3 was inhibited by SKF 525-A and ketoconazole, and partly by quinidine and sulfaphenazole. The oxidase activity affording 2,4-diOH-BP was inhibited by SKF 525-A, ketoconazole and α-naphthoflavone, and partly by sulfaphenazole. 3. The oxidase activity affording 5-OH-BP-3 was enhanced in liver microsomes of dexamethasone-, phenobarbital- and 3-methylcholanthrene-treated rats. The activity affording 2,4-diOH-BP was enhanced in liver microsomes of 3-methylcholanthrene- and phenobarbital-treated rats. 4. When examined recombinant rat cytochrome P450 isoforms catalyzing the metabolism of BP-3, 5-hydroxylation was catalyzed by P450 3A2, 1A1, 2B1, 2C6 and 2D1, while 4-desmethylation was catalyzed by P450 2C6 and 1A1.
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.
authors.forename: Nagisa
authors.initials: N
authors.lastname: Kamikyouden
authors.forename: Kazumi
authors.initials: K
authors.lastname: Sugihara
authors.forename: Yoko
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Naoto
authors.initials: N
authors.lastname: Uramaru
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Murahashi
authors.forename: Masanori
authors.initials: M
authors.lastname: Kuroyanagi
authors.forename: Seigo
authors.initials: S
authors.lastname: Sanoh
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohta
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: C587903:2,5-dihydroxy-4-methoxybenzophenone; D001577:Benzophenones; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; C005290:oxybenzone; D010088:Oxidoreductases