A 48-year-old Indian man with metastatic colorectal cancer is prescribed 5-fluorouracil (5-FU) as part of his chemotherapy regimen. His oncologist counsels him about the importance of adequate folate supplementation and mentions that a specific enzyme deficiency could increase his risk of severe 5-FU toxicity. Which enzyme deficiency would predispose this patient to enhanced 5-FU toxicity?

Explanation

## 5-Fluorouracil Metabolism and Toxicity Risk **Key Point:** **Dihydropyrimidine dehydrogenase (DPD) deficiency** is the critical enzyme deficiency that predisposes patients to severe, potentially life-threatening 5-FU toxicity. DPD catalyzes the catabolism (inactivation) of 5-FU, and its absence leads to drug accumulation and toxicity. ### 5-FU Metabolism Pathway ```mermaid flowchart LR A["5-Fluorouracil (5-FU)"]:::outcome --> B["Anabolism to active metabolites<br/>FdUMP, FdUTP"]:::action A --> C["Catabolism by DPD<br/>→ DHFU → β-Alanine"]:::action B --> D["Thymidylate synthase inhibition<br/>DNA synthesis ↓"]:::outcome C --> E["Inactivation & Excretion"]:::outcome F["DPD Deficiency"]:::urgent --> G["↓ Catabolism<br/>↑ 5-FU accumulation"]:::urgent G --> H["Severe toxicity:<br/>Myelosuppression, mucositis, diarrhea"]:::urgent ``` ### Why DPD Deficiency Causes Toxicity **High-Yield:** Approximately **3–5% of the population** carries DPD deficiency mutations (heterozygous or homozygous). In these patients: 1. 5-FU is not adequately catabolized 2. Drug accumulates to toxic concentrations 3. Prolonged exposure to active metabolites (FdUMP, FdUTP) occurs 4. Severe bone marrow suppression, mucositis, and diarrhoea develop **Clinical Pearl:** DPD testing (genotyping or phenotyping) is now recommended **before 5-FU administration** in many centres. Patients with DPD deficiency require either dose reduction (25–50%) or alternative chemotherapy. ### Mechanism of 5-FU Cytotoxicity Once activated, 5-FU's metabolites (FdUMP and FdUTP) inhibit: - **Thymidylate synthase** → blocks dTMP synthesis → impairs DNA synthesis - **Ribonucleotide reductase** → blocks dNTP production - **RNA polymerase** → impairs RNA synthesis This multi-target effect makes 5-FU highly effective but also highly toxic in DPD-deficient patients. ### Comparison of Antimetabolite Enzyme Targets | Enzyme | Drug | Function | Deficiency Effect | |--------|------|----------|-------------------| | **Dihydropyrimidine dehydrogenase (DPD)** | **5-FU** | **Catabolism/inactivation** | **↑ 5-FU toxicity** | | Dihydrofolate reductase | Methotrexate | Converts DHF → THF (cofactor synthesis) | ↑ MTX toxicity (rare) | | Thymidylate synthase | 5-FU (target) | dTMP synthesis | Resistance to 5-FU | | Ribonucleotide reductase | Gemcitabine, Ribavirin (target) | dNTP synthesis | Resistance to drug | **Mnemonic: "DPD Degrades — Deficiency = Danger"** — DPD breaks down 5-FU; without it, 5-FU accumulates and causes severe toxicity. [cite:KD Tripathi 8e Ch 65; Harrison 21e Ch 100]