Molecular biology and genetics: UGT1A1 and irinotecan: practice question

A Biochemistry question in the style of the NEET PG paper. Answer it first, then read why the right option is right and why each of the others is wrong.

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Biochemistry · Molecular biology and genetics: UGT1A1 and irinotecan

Sample item

A man with colon cancer develops severe neutropenia and diarrhoea after irinotecan. He is homozygous for the UGT1A1*28 variant. What is the mechanism?

Original practice item, not a recalled exam question. Nothing here is recorded.

The answer and the reasoning

B. Impaired glucuronidation of the active metabolite SN-38

Irinotecan is converted to the active metabolite SN-38, which is inactivated by UGT1A1-mediated glucuronidation. Reduced UGT1A1 expression allows SN-38 to accumulate and causes neutropenia and diarrhoea. The same enzyme is involved in Gilbert syndrome.

Option by option

  • A. Impaired methylation by thiopurine methyltransferase

    Thiopurine methyltransferase handles thiopurines, not irinotecan.

  • B. Impaired glucuronidation of the active metabolite SN-38 (correct)

    Correct. SN-38 is cleared by UGT1A1 and builds up when the enzyme is reduced.

  • C. Impaired activation of the prodrug by carboxylesterase

    Reduced activation would lower toxicity, not raise it.

  • D. Impaired breakdown of the drug by dihydropyrimidine dehydrogenase

    Dihydropyrimidine dehydrogenase handles fluorouracil, not irinotecan.

Source note: Original NextPrep sample item — pending expert review. This item is original practice material awaiting independent expert review, so confirm important facts in a standard textbook.

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Questions about this Biochemistry question

What is the answer to this Biochemistry question?

The best answer is B, Impaired glucuronidation of the active metabolite SN-38. Irinotecan is converted to the active metabolite SN-38, which is inactivated by UGT1A1-mediated glucuronidation.

Why is "Impaired methylation by thiopurine methyltransferase" not the answer?

Thiopurine methyltransferase handles thiopurines, not irinotecan.

Why is "Impaired activation of the prodrug by carboxylesterase" not the answer?

Reduced activation would lower toxicity, not raise it.

Why is "Impaired breakdown of the drug by dihydropyrimidine dehydrogenase" not the answer?

Dihydropyrimidine dehydrogenase handles fluorouracil, not irinotecan.

What concept does this question test?

It tests Molecular biology and genetics: UGT1A1 and irinotecan in Biochemistry. Reduced UGT1A1 expression allows SN-38 to accumulate and causes neutropenia and diarrhoea. The same enzyme is involved in Gilbert syndrome.

How hard is this question?

We tag it as a multi-step question: it asks you to combine more than one idea. The tag is our own editorial judgement, not an official difficulty rating, so read the reason for every option, not only the answer.

How should I study Molecular biology and genetics: UGT1A1 and irinotecan?

Build one table of enzyme deficiency, disease, inheritance and key finding, then revise it by spaced recall. Then use the flashcards and the other Biochemistry questions on this site to test what stuck.

Is this a real NEET PG question?

No. It is an original practice item (editorial status: sample, version 1). NextPrep does not publish recalled or leaked questions, and independent faculty review of this item has not been completed yet, so confirm important facts in a standard textbook.