Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans

Abstract

More than 20% of clinically used drugs are glucuronidated by a microsomal enzyme UDP-glucuronosyltransferase (UGT). Inhibition or induction of UGT can result in an increase or decrease in blood drug concentration. To avoid drug-drug interactions and adverse drug reactions in individuals, therefore, it is important to understand whether UGTs are involved in metabolism of drugs and drug candidates. While most of glucuronides are inactive metabolites, acyl-glucuronides that are formed from compounds with a carboxylic acid group can be highly toxic. Animals such as mice and rats are widely used to predict drug metabolism and drug-induced toxicity in humans. However, there are marked species differences in the expression and function of drug-metabolizing enzymes including UGTs. To overcome the species differences, mice in which certain drug-metabolizing enzymes are humanized have been recently developed. Humanized UGT1 (hUGT1) mice were created in 2010 by crossing Ugt1-null mice with human UGT1 transgenic mice in a C57BL/6 background. hUGT1 mice can be promising tools to predict human drug glucuronidation and acyl-glucuronide-associated toxicity. In this review article, studies of drug metabolism and toxicity in the hUGT1 mice are summarized. We further discuss research and strategic directions to advance the understanding of drug glucuronidation in humans.

Chronic polypharmacy impairs explorative behavior and reduces synaptic functions in young adult mice

“…Species differences have been pointed out by some reports, highlighting differences in drug metabolism between mice and humans [64]. To overcome possible limitations related to this, future studies involving mouse strains humanized for certain drug-metabolizing enzymes [65] may be necessary. Sex differences in pharmacokinetics, pharmacodynamics and ageing should be addressed in future studies.…”

A UPLC-MS-based metabolomics approach to reveal the attenuation mechanism of Caowu compatibility with Yunnan Baiyao

“…Glutaraldehyde acidication helps discharge toxic substances, drugs, or other substances that cannot be used as body energy sources. 45 Glucuronic acid is linked to other substances by glycosidic bonds, and the resulting glucuronides are much more water-soluble than the original substances, facilitating kidney excretion. 46 Compared with the control group, the 17-a-estradiol-3-glucuronide content in the CW group was signicantly lower, and gradually recovered aer processing and compatibility with YNBY, indicating that glutaraldehyde acidication gradually became normal during these processes, which might help excrete toxic substances.…”

The Role of CYP450 Drug Metabolism in Precision Cardio-Oncology

“…Likewise, clopidogrel can also inactivate CYP2C8, resulting in toxic levels of gemfibrozil [22]. Finally, UGT1 levels have been shown to inversely associate with development of a number of cancers (i.e., colon cancer, breast, bladder and biliary) in conditional UGT1 knockout mice [23]. Sulfonation reactions result in increased hydrophilicity and (usually) decreased pharmacological activity or inactivation of certain endogenous substances, such as thyroid hormones, steroids and monoamine transmitters.…”