van Beusekom C D, Fink-Gremmels J, Schrickx J A
Veterinary Pharmacology, Pharmacotherapy and Toxicology, Faculty of Veterinary Medicine, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.
J Vet Pharmacol Ther. 2014 Feb;37(1):18-24. doi: 10.1111/jvp.12067. Epub 2013 Jul 24.
This study aimed to assess the overall glucuronidation capacity of cats, using prototypic substrates identified for human UDP-glucuronosyltransferases (UGTs). To this end, Michaelis-Menten kinetics were established for the substrates using feline hepatic microsomal fractions, and results were compared with similar experiments carried out with dog liver microsomes. Cats are known for their low capacity of glucuronide formation, and UGT1A6 was found to be a pseudogene. However, functional studies with typical substrates were not performed and knowledge of the enzymology and genetics of other glucuronidation enzymes in felidae is lacking. The results of this study showed extremely low formation of naphthol-1-glucuronide (1.7 ± 0.4 nmol/mg protein/min), estradiol-17-glucuronide (<0.7 nmol/mg protein/min), and morphine-3-glucuronide (0.2 ± 0.03 nmol/mg protein/min), suggesting a lack of functional UGT1A6 and UGT2B7 homologues in the cat's liver. Dog liver microsomes were producing these glucuronides in much higher amounts. Glucuronide capacity was present for the substrates 17β-estradiol (estradiol-3-glucuronide, 2.9 ± 0.2 nmol/mg protein/min) and 4-methylumbelliferone (31.3 ± 3.3 nmol/mg protein/min), assuming that cats have functional homologue enzymes to at least the human UGT1A1 and probably other UGT1A isozymes. This implies that for new drugs, glucuronidation capacity has to be investigated on a substance-to-substance base. Knowledge of the glucuronidation rate of a drug provides the basis for pharmacokinetic modeling and as a result proper dosage regimens can be established to avoid undesirable drug toxicity in cats.
本研究旨在利用已确定的人尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）的原型底物，评估猫的整体葡萄糖醛酸化能力。为此，使用猫肝微粒体组分建立了底物的米氏动力学，并将结果与用狗肝微粒体进行的类似实验进行了比较。猫以其低葡萄糖醛酸苷形成能力而闻名，并且发现UGT1A6是一个假基因。然而，尚未对典型底物进行功能研究，并且缺乏猫科动物中其他葡萄糖醛酸化酶的酶学和遗传学知识。本研究结果显示，萘酚-1-葡萄糖醛酸苷（1.7±0.4 nmol/mg蛋白质/分钟）、雌二醇-17-葡萄糖醛酸苷（<0.7 nmol/mg蛋白质/分钟）和吗啡-3-葡萄糖醛酸苷（0.2±0.03 nmol/mg蛋白质/分钟）的形成极低，这表明猫肝脏中缺乏功能性UGT1A6和UGT2B7同源物。狗肝微粒体产生这些葡萄糖醛酸苷的量要高得多。对于底物17β-雌二醇（雌二醇-3-葡萄糖醛酸苷，2.9±0.2 nmol/mg蛋白质/分钟）和4-甲基伞形酮（31.3±3.3 nmol/mg蛋白质/分钟）存在葡萄糖醛酸化能力，假设猫至少具有与人UGT1A1功能同源的酶，可能还有其他UGT1A同工酶。这意味着对于新药，必须逐物质研究葡萄糖醛酸化能力。了解药物的葡萄糖醛酸化速率为药代动力学建模提供了基础，从而可以建立适当的给药方案以避免猫出现不良药物毒性。
