title: Mechanism for the protective effect of diallyl disulfide against cyclophosphamide acute urotoxicity in rats.
abstract: This study investigated the protective effects of diallyl disulfide (DADS) against cyclophosphamide (CP)-induced acute urotoxicity in rats. CP caused severe hemorrhagic cystitis as shown by significant increases in bladder weight, edema, and hemorrhage as well as increased urinary bladder epithelial cell apoptosis, protein expression of nuclear factor erythroid 2-related factor-2 (Nrf-2) and phase II enzymes (i.e.,
  quinone oxidoreductase-1 (NQO-1) and heme oxygenase-1 (HO-1)), immunostaining intensity of acrolein-protein adducts, and histopathological changes. The significant decreases in glutathione content and catalase, glutathione-S-transferase, and glutathione reductase activities and a significant increase in malondialdehyde content indicated that CP-induced bladder injury was mediated through oxidative stress. In contrast, pretreatment with DADS significantly attenuated the CP-induced urotoxic effects, including oxidative damage, histopathological lesions, apoptotic changes, and accumulation of acrolein-protein adducts in the bladder. DADS also significantly increased expression of CYP2B1/2, CYP3A1, Nrf-2, NQO-1, and HO-1 and significantly decreased expression of CYP2C11. These results indicate that DADS prevented CP-induced bladder toxicity, in part, by detoxifying acrolein. The protective effects of DADS may be due to its ability to decrease metabolic activation of CP by inhibiting CYP2C11 and inducing CYP3A1, and its potent antioxidant activity and antiapoptotic effects occurred via the Nrf-2-antioxidant response element pathway.
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Kim
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Lee
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Hyung-Seon
authors.initials: HS
authors.lastname: Baek
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea; Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Republic of Korea.
authors.forename: In-Sik
authors.initials: IS
authors.lastname: Shin
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Changjong
authors.initials: C
authors.lastname: Moon
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Chun-Sik
authors.initials: CS
authors.lastname: Bae
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Sung-Ho
authors.initials: SH
authors.lastname: Kim
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: toxkim@chonnam.ac.kr.
authors.forename: Jong-Choon
authors.initials: JC
authors.lastname: Kim
authors.affiliation: Biomedical Mouse Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Republic of Korea. Electronic address: hckim@kribb.re.kr.
authors.forename: Hyoung-Chin
authors.initials: HC
authors.lastname: Kim
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002374:Catalase / Q000378:metabolism; D003520:Cyclophosphamide / Q000633:toxicity*; D004220:Disulfides / Q000494:pharmacology*; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology
chemical_list: D000498:Allyl Compounds; D004220:Disulfides; D008315:Malondialdehyde; C028009:diallyl disulfide; D003520:Cyclophosphamide; D002374:Catalase; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase
keywords: Cyclophosphamide; Cytochrome P450; Diallyl disulfide; Nrf-2; Oxidative stress; Urotoxicity