Toxicological studies on feline cytochrome P450 associated with environmental chemical exposures 環境化学物質への曝露に関するネコのシトクロムP450の毒性学的研究

収集根拠 : 博士論文（自動収集）

資料形態 : テキストデータ

コレクション : 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文

Pet cats are frequently exposed to veterinary drugs and a variety of environmental compounds. They are also known to be especially sensitive to some drugs and chemical exposures. To identify their species’ sensitivity and toxicity caused by these environmental exposures, the knowledge on biotransformation ability for several xenobiotics in cats is thus required. Cytochrome P450 (CYP) is one of the most dominant metabolism enzymes in phase I and can be induced by numerous compounds. The study on feline CYP isozymes expression involved in chemical exposures is necessary for the prediction of adverse effects forward to drug development and veterinary clinic medication. In this study, polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and neonicotinoids are selected as the models of environmental compounds exposed to domestic cats worldwide. This present study aimed to elucidate the mRNA expression of the CYP1–CYP3 families in the cat tissues and CYP mRNA expression related to PCB and PBDE exposures, and to investigate the species differences in CYP involved in metabolism of PCBs and neonicotinoids between cats and other species. The in vivo exposures and in vitro CYP metabolism assay were conducted. Our results found that, in cats, the greatest abundance of CYP1–CYP3 (CYP1A2, CYP2A13, CYP2C41, CYP2D6, CYP2E1, CYP2E2, CYP2F2, CYP2F5, CYP2J2, CYP2U1, and CYP3A132) was expressed in the liver, but some extrahepatic isozymes were found in the kidney (CYP1A1), heart (CYP1B1), lung (CYP2B11 and CYP2S1) and small intestine (CYP3A131). Feline CYP1A1, CYP1A2 and CYP1B1 were significantly upregulated in the liver as well as in several tissues after once exposure to PCBs. However, these CYP1–CYP3 showed no significant difference in mRNA expression between control and BDE-209 exposure cats indicate that the chronic exposure of BDE-209 could not change CYP expression in the liver of cats. The study of in vitro CYP-mediated PCB metabolism found that the OH-PCB profiles between cats and dogs were similar and 4ʹOH-CB18 was major metabolite. These findings combined with in silico docking simulation indicated that cat CYP3A and dog CYP3A/1A1 could mainly catalyze most PCBs, particularly PCB18, while CYP1A1 in cats and CYP1A2/2B in dogs may be less players for the metabolism of some PCBs. The levels of OH-PCB formation indicate feline CYPs have lower affinity to PCBs than those in dogs. The kinetic parameters of CYP metabolizing neonicotinoids indicate cats have particularly low CYP activity for metabolism of neonicotinoids in comparison to rats and humans. The feline glucuronidation deficiency together with all our findings suggested that PCBs and neonicotinoids may be metabolized less in cats as compared to other species.

(主査) 教授 石塚 真由美, 教授 滝口 満喜, 准教授 池中 良徳, 准教授 水川 葉月（愛媛大学）

獣医学研究科（獣医学専攻）