Molecular genetic basis for deficient acetaminophen glucuronidation by cats: UGT1A6 is a pseudogene, and evidence for reduced diversity of expressed hepatic UGT1A isoforms
Molecular genetic basis for deficient acetaminophen glucuronidation by cats: UGT1A6 is a pseudogene, and evidence for reduced diversity of expressed hepatic UGT1A isoforms
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DOI：
10.1097/00008571-200006000-00009
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发表时间：
2000-06-01
期刊：
影响因子：
--
通讯作者：
Greenblatt, DJ
中科院分区：
文献类型：
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作者：
Court, MH;Greenblatt, DJ
与大多数其他哺乳动物物种相比，家猫对平面酚类异生物质进行葡萄糖醛酸化的能力明显较低。这项研究的目的是确定这种异常的机制基础。目前对 UDP-葡萄糖醛酸基转移酶 (UGT) 同工型底物特异性的了解表明，猫可能缺乏或表达较差的 UGT1A6。最初，使用一种新的克隆技术来鉴定猫肝脏中表达的 UGT1A 基因。只能区分两种独特的 UGT1A 同工型。第一个（28% 的克隆）与 UGT1A1（胆红素-UGT）最同源，而第二个（72% 的克隆）与多个同工型表现出同源性，但无法明确识别，并被指定为猫 UGT1A02，Southern 印迹分析证实猫基因组中存在单个 UGT1A6 同源区域。随后对整个 UGT1A6 外显子 1 编码区的克隆和测序揭示了五个有害的基因突变。通过对其他不相关的活猫的 UGT1A6 外显子 1 进行测序，发现了相同的突变。这 5 个基因损伤中的 4 个也在虎猫 (Leopardus wiedii) 的 UGT1A6 外显子 1 区域中被发现。最后，来自四只不同猫的肝脏 mRNA 的 RT-PCR 证实了 UGT1A1 和 UGT1A02 的存在，但没有 UGT1A6。总之，UGT1A6 在家猫和至少一种其他系统发育相关物种中是假基因。此外，与其他物种相比，猫的 UGT1A 同工型表达模式似乎不太多样化。这种差异很可能反映了猫科动物的高度肉食性饮食以及由此产生的植物抗毒素的最低限度暴露。药物遗传学 10:355-369 (C) 2000 Lippincott Williams & Wilkins。
The domestic cat has a significantly lower capacity to glucuronidate planar phenolic xenobiotics compared with most other mammalian species. The aim of this study was to determine the mechanistic basis for this anomaly. Current knowledge of the substrate specificity of UDP-glucuronosyl transferase (UGT) isoforms indicates that the cat may either lack or poorly express UGT1A6, Initially, a novel cloning technique was used to identify UGT1A genes expressed in cat liver. Only two unique UGT1A isoforms could be discriminated.. The first (28% of clones) was most homologous to UGT1A1 (the bilirubin-UGT), while the second (72% of clones) showed homology to several isoforms, but could not be unambiguously identified, and was designated cat UGT1A02, Southern blot analysis confirmed the presence of a single UGT1A6-homologous region in the cat genome. Subsequent cloning and sequencing of the entire UGT1A6 exon 1 coding region revealed five deleterious genetic mutations. Identical mutations were found by sequencing of UGT1A6 exon 1 from live other unrelated cats. Four of these five genetic lesions were also identified in the UGT1A6 exon 1 region of a margay (Leopardus wiedii). Finally, RT-PCR of liver mRNA from four different cats confirmed the presence of UGT1A1 and UGT1A02, but not UGT1A6, In conclusion, UGT1A6 is a pseudogene in the domestic cat and in at least one other phylogenetically related species. Furthermore, cats appear to have a less diverse pattern of UGT1A isoform expression compared with other species, Such differences most likely reflect the highly carnivorous diet of Feliform species and resultant minimal exposure to phytoalexins. Pharmacogenetics 10:355-369 (C) 2000 Lippincott Williams & Wilkins.