title: Differential Effects of Sunitinib on the Expression Profiles of Xenobiotic-Metabolizing Enzymes and Transporters in Rat Liver and Kidneys.
abstract: Sunitinib (SUN) is a multi-targeted tyrosine kinase inhibitor that was recently approved for the treatment of gastrointestinal tract and renal cancers. To date, very little is known about the effects of SUN on the expression of hepatic and renal xenobiotic-metabolizing enzymes (XMEs) and transporters. The present study was designed to investigate the capacity of chronic SUN treatment to modulate the mRNA and protein expression levels of phase I cytochrome P450 (CYP), phase II conjugating enzymes, and phase III transporters in rat liver and kidneys. For this purpose, SUN (25, 50 and 100 mg/kg) was injected IP into Wistar albino rats for 4 weeks; thereafter, the mRNA and protein expression levels of several XMEs and transporters were determined by RT-PCR and Western blot analysis, respectively. Real-time PCR analysis showed that SUN significantly induced the hepatic and renal CYP1A1, 1A2, 1B1, 2E1 and 4F4, whereas it inhibited CYP2C11 and 4A2. Furthermore, SUN specifically induced renal, but not hepatic, CYP2J3 and 3A2, while it induced only hepatic CYP4A1. With regard to phase II, SUN induced hepatic GSTA1 and UGT1A and renal NQO1 and UGT1A mRNA levels, whereas it inhibited renal GST1A expression. On the other hand, both renal and hepatic P-gp, MRP2 and BCRP transporters were significantly induced by SUN at the mRNA and protein expression levels. Importantly, these differential effects were associated with changes in oxidative stress genes and lipid peroxidation levels. In conclusion, SUN can serve as XME and transporters modulator, which potentially may counteract the efficacy of the treatment, adverse reactions and drug interactions in SUN treatment.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Korashy
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Mushtaq A
authors.initials: MA
authors.lastname: Ansari
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Zaid H
authors.initials: ZH
authors.lastname: Maayah
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Faisal
authors.initials: F
authors.lastname: Imam
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Raish
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ibraheem M
authors.initials: IM
authors.lastname: Attafi
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Naif O
authors.initials: NO
authors.lastname: Alharbi
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Bader A
authors.initials: BA
authors.lastname: Moraished
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000072470:Cytochrome P450 Family 4 / Q000235:genetics / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D039181:Steroid 16-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077210:Sunitinib; D059467:Transcriptome; D015262:Xenobiotics / Q000378:metabolism; D000099148:UGT1A1 Enzyme
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System; D000072467:Cytochrome P450 Family 2; D000072470:Cytochrome P450 Family 4; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D007211:Indoles; D007527:Isoenzymes; D016660:NAD(P)H Dehydrogenase (Quinone); D011758:Pyrroles; D012333:RNA, Messenger; D039181:Steroid 16-alpha-Hydroxylase; D000077210:Sunitinib; D015262:Xenobiotics; C423013:Abcc2 protein, rat; C489249:Abcg2 protein, rat; C499946:Ugt1a1 protein, rat; D000099148:UGT1A1 Enzyme; C450279:CYP2C11 protein, rat; C017170:Cyp1a2 protein, rat; C585499:Cyp1b1 protein, rat; C465481:Cyp4f4 protein, rat; C465388:cytochrome P-450 CYP4A2 (rat); C507703:NQO1 protein, rat; C119995:glutathione S-transferase alpha