title: Ursodeoxycholic acid inhibits overexpression of P-glycoprotein induced by doxorubicin in HepG2 cells.
abstract: The hepatoprotective action of ursodeoxycholic acid (UDCA) was previously suggested to be partially dependent on its antioxidative effect. Doxorubicin (DOX) and reactive oxygen species have also been implicated in the overexpression of P-glycoprotein (P-gp), which is encoded by the MDR1 gene and causes antitumor multidrug resistance. In the present study, we assessed the effects of UDCA on the expression of MDR1 mRNA, P-gp, and intracellular reactive oxygen species levels in DOX-treated HepG2 cells and compared them to those of other bile acids. DOX-induced increases in reactive oxygen species levels and the expression of MDR1 mRNA were inhibited by N-acetylcysteine, an antioxidant, and the DOX-induced increase in reactive oxygen species levels and DOX-induced overexpression of MDR1 mRNA and P-gp were inhibited by UDCA. Cells treated with UDCA showed improved rhodamine 123 uptake, which was decreased in cells treated with DOX alone. Moreover, cells exposed to DOX for 24h combined with UDCA accumulated more DOX than that of cells treated with DOX alone. Thus, UDCA may have inhibited the overexpression of P-gp by suppressing DOX-induced reactive oxygen species production. Chenodeoxycholic acid (CDCA) also exhibited these effects, whereas deoxycholic acid and litocholic acid were ineffective. In conclusion, UDCA and CDCA had an inhibitory effect on the induction of P-gp expression and reactive oxygen species by DOX in HepG2 cells. The administration of UDCA may be beneficial due to its ability to prevent the overexpression of reactive oxygen species and acquisition of multidrug resistance in hepatocellular carcinoma cells.
authors.affiliation: Division of Medical Laboratory Sciences, Department of Radiological and Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-minami, Higashi-ku, Nagoya 461-8673, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Komori
authors.affiliation: Division of Medical Laboratory Sciences, Department of Radiological and Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-minami, Higashi-ku, Nagoya 461-8673, Japan.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Arisawa
authors.affiliation: Division of Medical Laboratory Sciences, Department of Radiological and Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-minami, Higashi-ku, Nagoya 461-8673, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Takai
authors.affiliation: Division of Medical Laboratory Sciences, Department of Radiological and Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-minami, Higashi-ku, Nagoya 461-8673, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yokoyama
authors.affiliation: Division of Medical Laboratory Sciences, Department of Radiological and Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-minami, Higashi-ku, Nagoya 461-8673, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Honda
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ishigami
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Katano
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Goto
authors.affiliation: Division of Medical Laboratory Sciences, Department of Radiological and Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-minami, Higashi-ku, Nagoya 461-8673, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ueyama
authors.affiliation: Division of Medical Laboratory Sciences, Department of Radiological and Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-minami, Higashi-ku, Nagoya 461-8673, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Division of Medical Laboratory Sciences, Department of Radiological and Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-minami, Higashi-ku, Nagoya 461-8673, Japan. Electronic address: wakusawa@met.nagoya-u.ac.jp.
authors.forename: Shinya
authors.initials: S
authors.lastname: Wakusawa
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D056945:Hep G2 Cells; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014580:Ursodeoxycholic Acid; D004317:Doxorubicin
keywords: Bile acids; Chenodeoxycholic acid (PubChem CID: 10133); Deoxycholic acid (PubChem CID: 222528); Doxorubicin (PubChem CID: 31703); Lithocholic acid (PubChem CID: 9903); MDR1; P-Glycoprotein; Reactive oxygen species; Rhodamine 123 (PubChem CID: 65217); Ursodeoxycholic acid; Ursodeoxycholic acid (PubChem CID: 31401)