Deficiency of which of the following enzyme leads to toxicity of 5-fluorouracil?
**Core Concept**
5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent that acts as an antimetabolite by inhibiting thymidylate synthase, thereby disrupting DNA synthesis. Its toxicity is related to the accumulation of its metabolite, 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which forms a stable complex with thymidylate synthase.
**Why the Correct Answer is Right**
The correct answer is related to the enzyme dihydropyrimidine dehydrogenase (DPD). DPD is responsible for the initial catabolism of 5-FU, converting it into its inactive metabolite 5,6-dihydro-5-fluorouracil (5,6-DHFU). In patients with DPD deficiency, the levels of 5-FU increase, leading to its toxic effects, including gastrointestinal toxicity, myelosuppression, and neurotoxicity. FdUMP, the active metabolite of 5-FU, accumulates and inhibits thymidylate synthase, leading to the disruption of DNA synthesis and repair.
**Why Each Wrong Option is Incorrect**
* **Option A:** Thymidylate synthase deficiency would not lead to 5-FU toxicity, as it would be the enzyme inhibited by the drug, not the cause of its toxicity.
* **Option B:** Dihydrofolate reductase (DHFR) is an enzyme involved in the folate metabolism pathway, but its deficiency is not directly related to 5-FU toxicity.
* **Option D:** Aldehyde dehydrogenase (ALDH) is an enzyme involved in the metabolism of various aldehydes, but it is not directly involved in the metabolism of 5-FU.
**Clinical Pearl / High-Yield Fact**
DPD deficiency is a rare genetic disorder that can lead to severe toxicity from 5-FU. Patients with DPD deficiency may require dose adjustments or alternative chemotherapeutic agents to minimize the risk of toxicity.
**Correct Answer: C. Dihydropyrimidine dehydrogenase (DPD)**