A 12-year-old boy is evaluated due to fever, fatigue, and easy bruising. Physical examination shows pallor, generalized lymphadenopathy, and bone tenderness. Laboratory evaluation reveals anemia, thrombocytopenia, and leukocytosis with atypical lymphoblasts. Bone marrow biopsy is consistent with acute lymphoblastic leukemia. The patient is treated with combination chemotherapy, and 6-mercaptopurine is administered for maintenance of remission. Which of the following enzymes inactivates this drug?

Question

A 12-year-old boy is evaluated due to fever, fatigue, and easy bruising.  Physical examination shows pallor, generalized lymphadenopathy, and bone tenderness.  Laboratory evaluation reveals anemia, thrombocytopenia, and leukocytosis with atypical lymphoblasts.  Bone marrow biopsy is consistent with acute lymphoblastic leukemia.  The patient is treated with combination chemotherapy, and 6-mercaptopurine is administered for maintenance of remission.  Which of the following enzymes inactivates this drug?

Quizplus · Accepted Answer

11ec160b_3bdf_1635_9249_7312bd24c2ea_MD0001_00 6-mercaptopurine (6-MP) can be administered directly or in its prodrug form (ie, azathioprine). Following ingestion, 6-MP is converted by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) into 6-thioguanine (6-TG) active metabolites (Choice C). The 6-TG metabolites are purine analogues that act as false nucleotides to disrupt DNA and RNA synthesis and inhibit the proliferation of hematopoietic cells, a useful effect in the treatment of autoimmune disease, organ transplant rejection, and some types of cancer (eg, leukemia). 6-MP is metabolized into inactive metabolites by 2 different enzymes, xanthine oxidase and thiopurine methyltransferase (TPMT), both of which are clinically important. Coadministration of 6-MP with a xanthine oxidase inhibitor (eg, allopurinol, febuxostat) slows the inactivation of 6-MP and shunts metabolism toward the production of 6-TG active metabolites; therefore, the dose of 6-MP must be significantly reduced. In addition, roughly 12% of the population has a genetic mutation resulting in low or absent activity of TPMT, creating a high risk of toxicity with the administration of 6-MP. Therefore, some clinicians recommend that patients undergo genetic testing for TPMT activity prior to initiating 6-MP (or azathioprine) therapy. (Choice A) Adenosine deaminase (ADA) converts adenosine to inosine as part of purine metabolism. This enzyme is deficient in severe combined immunodeficiency but may be overexpressed in some malignancies. Cladribine, which is used in the treatment of hairy cell leukemia, is a cytotoxic purine analogue resistant to degradation by ADA. (Choice B) Methotrexate is used in the treatment of cancer and rheumatologic disease. It inhibits dihydrofolate reductase, thereby blocking the conversion of dihydrofolate to tetrahydrofolate and disrupting the synthesis of thymidine and, to a lesser extent, purines. (Choice D) Monoamine oxidase inhibitors are used in the treatment of atypical depression; these agents inhibit degradation of the neurotransmitters norepinephrine, dopamine, and serotonin. (Choice E) Cyclophosphamide, used to treat many types of cancer, requires bioactivation by the cytochrome P-450 mixed-function oxidase system. (Choice F) Topoisomerase II is inhibited by the chemotherapeutic agents etoposide and teniposide. Educational objective: 6-mercaptopurine (6-MP) is an immunosuppression drug that is inactivated by 2 enzymes, xanthine oxidase and thiopurine methyltransferase. Reduced function of either enzyme causes increased levels of the active metabolites of 6-MP, leading to increased immunosuppression and risk of toxicity. __________ References: Implementation of TPMT testing. (http://www.ncbi.nlm.nih.gov/pubmed/23962279)

A 12-Year-Old Boy Is Evaluated Due to Fever, Fatigue, and Easy