Ugt1a1-KO Mouse

Ugt1a1, encoding uridine diphosphate glucuronosyl transferase 1A1, is a key enzyme in Phase II metabolic processes. It is involved in the metabolism and glucuronidation of certain drugs, and is the only enzyme capable of metabolizing and detoxifying bilirubin [3,5]. Genetic polymorphisms of Ugt1a1 can impact drug plasma concentrations and may be linked to treatment outcomes [3].

UGT1A1 enzyme deficiency, caused by gene variants like UGT1A1*6, *28, and *37, increases the risk of irinotecan-induced toxicity such as (febrile) neutropenia or diarrhoea. Homozygous or compound heterozygous carriers of these allele variants are UGT1A1 poor metabolisers. Guidelines recommend a 70% starting dose in poor metabolisers for irinotecan treatment [1]. Also, UGT1A1*6 and *28 genotyping is considered essential prior to starting irinotecan treatment to prevent severe toxicity [1,2,4]. Moreover, UGT1A1 G71R mutation is associated with hyperbilirubinemia in Dong neonates [6].

In conclusion, Ugt1a1 plays a crucial role in drug metabolism and bilirubin detoxification. Studies on Ugt1a1, especially those focusing on gene variants like UGT1A1*6 and *28, have significant implications for preventing drug-induced toxicities in cancer treatment, particularly with irinotecan, and understanding the pathogenesis of hyperbilirubinemia [1,2,4,6].

References:

1. Hulshof, Emma C, Deenen, Maarten J, Nijenhuis, Marga, Guchelaar, Henk-Jan, Swen, Jesse J. 2022. Dutch pharmacogenetics working group (DPWG) guideline for the gene-drug interaction between UGT1A1 and irinotecan. In European journal of human genetics : EJHG, 31, 982-987. doi:10.1038/s41431-022-01243-2. https://pubmed.ncbi.nlm.nih.gov/36443464/

2. Hulshof, Emma C, Deenen, Maarten J, Guchelaar, Henk-Jan, Gelderblom, Hans. 2020. Pre-therapeutic UGT1A1 genotyping to reduce the risk of irinotecan-induced severe toxicity: Ready for prime time. In European journal of cancer (Oxford, England : 1990), 141, 9-20. doi:10.1016/j.ejca.2020.09.007. https://pubmed.ncbi.nlm.nih.gov/33125947/

3. Goon, Chong Ping, Wang, Ling Zhi, Wong, Fang Cheng, Ho, Paul Chi-Lui, Goh, Boon Cher. . UGT1A1 Mediated Drug Interactions and its Clinical Relevance. In Current drug metabolism, 17, 100-6. doi:. https://pubmed.ncbi.nlm.nih.gov/26526830/

4. Matsuoka, Ayumu, Ando, Yuichi. . [UGT1A1 Genotyping for Proper Use of Irinotecan]. In Rinsho byori. The Japanese journal of clinical pathology, 63, 876-82. doi:. https://pubmed.ncbi.nlm.nih.gov/26591441/

5. Liu, Dan, Yu, Qi, Ning, Qing, Liu, Zhongqiu, Song, Jie. 2021. The relationship between UGT1A1 gene & various diseases and prevention strategies. In Drug metabolism reviews, 54, 1-21. doi:10.1080/03602532.2021.2001493. https://pubmed.ncbi.nlm.nih.gov/34807779/

6. Yao, Xuan, Zhong, Dan-Ni, Peng, Yun-Cong. . [UGT1A1 gene mutations in Chinese Dong neonates in Sanjiang, Guangxi]. In Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics, 24, 792-796. doi:10.7499/j.issn.1008-8830.2202127. https://pubmed.ncbi.nlm.nih.gov/35894195/