Diclofenac‐induced adverse drug reactions and hyperbilirubinemia caused by a variant gene

• Published in: The Kaohsiung journal of medical sciences 2022-03, Vol.38 (3), p.286-287
• Main Authors: Chen, En‐Sung, Lee, Chia‐Long, Tsui, Ko‐Chung, Huang, Ching‐Shan
• Format: Article
• Language: English
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - adverse effects; Anti-inflammatory drugs; Aspartate; Conflicts of interest; Diclofenac - adverse effects; Drug-Related Side Effects and Adverse Reactions; Genetic research; Humans; Hyperbilirubinemia; Hyperbilirubinemia - chemically induced; Hyperbilirubinemia - genetics; Laboratories; Liver; Metabolism; Nonsteroidal anti-inflammatory drugs; Surveys
• ISSN: 1607-551X; 2410-8650
• DOI: 10.1002/kjm2.12472

To study the chemical pathology of the hyperbilirubinemia, we re-valuated the patient's Hb, total bilirubin, direct bilirubin, AST, and ALT levels and analyzed the uridine diphosphate-glucuronosyltransferase (UGT) 1A1 gene 1 and eight single nucleotide polymorphisms (SNPs) related to diclofenac metabolism, 2,3 namely linked polymorphisms 416 G>A and 1196 A>G in the cytochrome P 450 (CYP) 2C8 gene (CYP2C8*3), 430 C>T (CYP2C9*2), and 1075 A>C (CYP2C9*3) in the CYP2C9 gene, 352 A>G (CYP3A4*4), 653 C>G (CYP3A4*5), and 20070 T>C (CYP3A4*18A) in the CYP3A4 gene, 802 C>T in the UGT2B7 gene (UGT2B7*2a), and −118 T9>T10 in the UGT1A9 gene (UGT1A9*1u). Four exons (exons 2–5) are common to the alternatively spliced products transcribed from the UGT1A gene locus, namely UGT1A1 and UGT1A3–UGT1A10. [...]the amino acid variant, p.Pro364Leu, should be present in other functional UGT1A products, including UGT1A9. Because the p.Pro364Leu variant UGT1A9 protein exhibited lower glucuronosyltransferase activity on acetaminophen and propofol than its wild-type counterpart (5.0% and 29.0% of wild-type UGT1A9 activity, respectively 4), patients with 1091 TT in UGT1A1 likely metabolize diclofenac at a lower rate than those with the wild type gene, and the diclofenac is thus retained at a higher blood concentration or for an extended duration, leading to liver injury (from elevated bilirubin levels, although liver enzymes may be normal) in susceptible patients.