2,5-Dihydroxy-4-methoxybenzophenone: a novel major in vitro metabolite of benzophenone-3 formed by rat and human liver microsomes

作者：Kamikyouden Nagisa; Sugihara Kazumi; Watanabe Yoko; Uramaru Naoto; Murahashi Tsuyoshi; Kuroyanagi Masanori; Sanoh Seigo; Ohta Shigeru; Kitamura Shigeyuki^*

来源：Xenobiotica, 2013, 43(6): 514-519.

DOI：10.3109/00498254.2012.742217

• Benzophenone-3
• in vitro metabolism
• rat liver microsomes
• human liver microsomes
• Cytochrome P450

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. %26lt;br%26gt;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 a-naphthoflavone, and partly by sulfaphenazole. %26lt;br%26gt;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. %26lt;br%26gt;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.

• 出版日期2013-6