title: Inhibitory effects of citrus fruits on cytochrome P450 3A (CYP3A) activity in humans.
abstract: The capacities of citrus fruits to inhibit midazolam 1'-hydroxylase activity of cytochrome P450 3A (CYP3A) expressed in human liver microsomes were evaluated. Eight citrus fruits such as ama-natsu, banpeiyu, Dekopon, hassaku, hyuga-natsu, completely matured kinkan (Tamatama), takaoka-buntan and unshu-mikan were tested. We also examined the inhibition of CYP3A activity by grapefruit (white) and grapefruit juice (white, Tropicana-Kirin). The addition of a fruit juice prepared from banpeiyu, hassaku, takaoka-buntan or Tamatama caused the inhibition of the microsomal CYP3A activity. The inhibition depended on the amount of a fruit juice added to the incubation mixture (2.5 and 5.0%, v/v). The fruit juice from banpeiyu showed the most potent inhibition of CYP3A. The addition of a banpeiyu juice (5.0%, v/v) resulted in the inhibition of midazolam 1'-hydroxylase activity to about 20% of control without a fruit juice. The elongation of the preincubation period of a fruit juice from banpeiyu (5.0%, v/v) with the microsomal fraction (5 to 15 min) led to the enhancement of the CYP3A inhibition (5% of control). Thus, we discovered ingredients of banpeiyu to be inhibitor(s) or mechanism-based inhibitor(s) of human CYP3A activity, but the inhibitory effects of them were somewhat lower than those of grapefruit.
authors.affiliation: Department of Pharmacy, Miyazaki Medical College Hospital, Miyazaki-gun, Japan. kfujita@post.miyazaki-med.ac.jp
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Fujita
authors.forename: Muneaki
authors.initials: M
authors.lastname: Hidaka
authors.forename: Norito
authors.initials: N
authors.lastname: Takamura
authors.forename: Keishi
authors.initials: K
authors.lastname: Yamasaki
authors.forename: Tomomi
authors.initials: T
authors.lastname: Iwakiri
authors.forename: Manabu
authors.initials: M
authors.lastname: Okumura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kodama
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Tsuyomu
authors.initials: T
authors.lastname: Ikenoue
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Arimori
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D001628:Beverages; D002957:Citrus / Q000737:chemistry*; D051544:Cytochrome P-450 CYP3A; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008874:Midazolam / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam