Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae: Phylogenetic Timing and the Role of Hypercarnivory

The domestic cat (Felis catus) shows remarkable sensitivity to the adverse effects of phenolic drugs, including acetaminophen and aspirin, as well as structurally-related toxicants found in the diet and environment. This idiosyncrasy results from pseudogenization of the gene encoding UDP-glucuronosyltransferase (UGT) 1A6, the major species-conserved phenol detoxification enzyme. Here, we established the phylogenetic timing of disruptive UGT1A6 mutations and explored the hypothesis that gene inactivation in cats was enabled by minimal exposure to plant-derived toxicants. Fixation of the UGT1A6 pseudogene was estimated to have occurred between 35 and 11 million years ago with all extant Felidae having dysfunctional UGT1A6. Out of 22 additional taxa sampled, representative of most Carnivora families, only brown hyena (Parahyaena brunnea) and northern elephant seal (Mirounga angustirostris) showed inactivating UGT1A6 mutations. A comprehensive literature review of the natural diet of the sampled taxa indicated that all species with defective UGT1A6 were hypercarnivores (>70% dietary animal matter). Furthermore those species with UGT1A6 defects showed evidence for reduced amino acid constraint (increased dN/dS ratios approaching the neutral selection value of 1.0) as compared with species with intact UGT1A6. In contrast, there was no evidence for reduced amino acid constraint for these same species within UGT1A1, the gene encoding the enzyme responsible for detoxification of endogenously generated bilirubin. Our results provide the first evidence suggesting that diet may have played a permissive role in the devolution of a mammalian drug metabolizing enzyme. Further work is needed to establish whether these preliminary findings can be generalized to all Carnivora.

家猫（Felis catus）对包括对乙酰氨基酚（acetaminophen）、阿司匹林（aspirin）在内的酚类药物（phenolic drugs），以及膳食与环境中存在的结构相似有毒物质的不良反应展现出显著敏感性。这种特异性源于编码尿苷二磷酸葡萄糖醛酸转移酶1A6（UDP-glucuronosyltransferase 1A6，UGT1A6）的基因发生假基因化——该酶是物种保守的主要苯酚解毒酶。本研究明确了UGT1A6失活突变的系统发育时间，并验证了“家猫的该基因失活得益于其接触植物源有毒物质极少”这一假说。经估算，UGT1A6假基因的固定发生于3500万至1100万年前，所有现存猫科动物均携带功能异常的UGT1A6。在覆盖多数食肉目（Carnivora）科别的22个额外采样类群中，仅棕鬣狗（Parahyaena brunnea）与北象海豹（Mirounga angustirostris）存在UGT1A6失活突变。对采样类群天然食性的全面文献综述显示，所有UGT1A6功能缺陷的物种均为超食肉动物（hypercarnivores，膳食动物来源占比＞70%）。此外，与携带完整UGT1A6的物种相比，UGT1A6功能缺陷物种表现出氨基酸约束减弱的证据——其dN/dS比值（dN/dS ratios）趋近于中性选择值1.0。与之形成对比的是，在编码内源性胆红素（bilirubin）解毒酶的UGT1A1基因区域中，上述功能缺陷物种并未表现出氨基酸约束减弱的迹象。本研究首次提供证据表明，饮食可能在哺乳动物药物代谢酶（drug metabolizing enzyme）的退化过程中发挥了许可性作用。未来仍需开展进一步研究，以明确这些初步发现是否可推广至所有食肉目类群。