Journal of Pharmacogenomics & Pharmacoproteomics

Role of UGT1A1 Polymorphism in Irinotecan-Induced Toxicity in Colorectal Cancer Treatment

Hanae Morimoto^* Department of Molecular Pharmacology, Kyoto Biomedical University, Kyoto, Japan
^*Correspondence: Hanae Morimoto, Department of Molecular Pharmacology, Kyoto Biomedical University, Kyoto, Japan, Email:

Received: 26-Feb-2025, Manuscript No. JPP-25-29327; Editor assigned: 28-Mar-2025, Pre QC No. JPP-25-29327(PQ); Reviewed: 14-Mar-2025, QC No. JPP-25-29327; Revised: 21-Mar-2025, Manuscript No. JPP-25-29327(R); Published: 28-Mar-2025, DOI: 10.4172/2153-0645.25.16.125

Description

Irinotecan, a topoisomerase I inhibitor, is a cornerstone chemotherapeutic agent for the treatment of metastatic colorectal cancer. Despite its efficacy, its clinical use is often limited by unpredictable severe toxicities such as neutropenia and diarrhea. Over the past decade, pharmacogenomic research has identified a strong correlation between polymorphisms in the UDP-glucuronosyltransferase 1A1 gene and the pharmacokinetics of irinotecan, providing a rationale for genotype-guided dosing to optimize treatment outcomes.

In Japanese populations, however, the UGT1A1 *6 variant, a missense mutation in exon 1, plays a more critical role. Unlike the *28 variant that predominates in Caucasian populations, UGT1A1*6 is more prevalent in East Asians and is also associated with reduced enzymatic activity. Studies involving colorectal cancer patients in Japan and South Korea have shown that the presence of either *6 or *28 alleles, particularly in the homozygous or compound heterozygous states, correlates strongly with severe hematologic toxicity following irinotecan administration.

This prompted the Japanese Ministry of Health to recommend UGT1A1 genotyping before initiating irinotecan therapy, especially when high doses are planned. These findings have since influenced treatment guidelines and led to dose modifications tailored to the patient's genetic profile. However, despite this warning, genotyping is not yet uniformly implemented in clinical oncology, often due to cost, accessibility issues, and limited awareness among practitioners.

The integration of UGT1A1 genotyping into clinical workflows is gaining momentum with the advent of next-generation sequencing panels that simultaneously test for multiple Pharmacogenom. These platforms enable comprehensive risk assessment not only for irinotecan but also for other medications metabolized through glucuronidation. In Japan, a government- funded pilot project is evaluating the cost-benefit ratio of implementing pharmacogenomic testing in all cancer patients receiving chemotherapy, with initial data suggesting a decrease in hospital readmissions due to drug-related adverse events.

The impact of UGT1A1 polymorphisms extends beyond toxicity management. Emerging evidence suggests that high systemic exposure to SN-38 in patients with low UGT1A1 activity may paradoxically enhance treatment efficacy by increasing tumor cytotoxicity. This dual effect presents a therapeutic dilemma: while reduced enzyme activity raises toxicity risk, it may also contribute to better tumor response. Thus, pharmacogenomic data must be interpreted in the context of both safety and efficacy, highlighting the need for individualized dose titration strategies rather than blanket dose reductions.

Additionally, Pharmacoproteomic research is uncovering potential biomarkers that may complement UGT1A1 genotyping. Quantitative proteomic studies have identified differential expression patterns of UGT1A1 and related enzymes in tumor tissues versus normal tissues, offering novel insights into interpatient variability. These findings may pave the way for integrated proteogenomic approaches in precision oncology.

In conclusion, UGT1A1 polymorphisms, particularly *6 and *28, play a pivotal role in determining irinotecan toxicity and offer a compelling case for preemptive pharmacogenomic screening. As colorectal cancer treatment continues to evolve toward precision medicine, the incorporation of UGT1A1 genotyping into routine practice holds significant promise for enhancing patient safety and therapeutic efficacy. Bridging the gap between genomic knowledge and clinical implementation remains a key challenge, but ongoing efforts in policy-making, education, and technological innovation are steadily moving the field forward.