A 23-year-old woman comes to the emergency department with vaginal bleeding and lower abdominal cramps. Her last menstrual period was 6 weeks ago, and a home pregnancy test was positive. She has no medical history and does not use tobacco or alcohol. Pelvic ultrasonography reveals a gestational sac in the left fallopian tube without evidence of rupture. A single dose of methotrexate is administered to treat her condition. Which of the following substances will most likely accumulate in embryonic tissues as a result of treatment?

Question

A 23-year-old woman comes to the emergency department with vaginal bleeding and lower abdominal cramps.  Her last menstrual period was 6 weeks ago, and a home pregnancy test was positive.  She has no medical history and does not use tobacco or alcohol.  Pelvic ultrasonography reveals a gestational sac in the left fallopian tube without evidence of rupture.  A single dose of methotrexate is administered to treat her condition.  Which of the following substances will most likely accumulate in embryonic tissues as a result of treatment?

Quizplus · Accepted Answer

11ec160b_3be5_30c0_9249_b5b472b61e8b_MD0001_00 Methotrexate (MTX), a folate antagonist, is the drug of choice for non-surgical treatment of an early, unruptured ectopic pregnancy. Folic acid is a required precursor to nucleic acid synthesis. Barriers to its metabolism are especially effective in hindering the growth of rapidly proliferating cells such as in a developing embryo or certain types of cancer. Normally, folic acid is reduced to dihydrofolate (DHF) by dihydrofolate reductase and then reduced further to tetrahydrofolate (THF), an integral precursor of DNA synthesis. MTX is structurally similar to folic acid and competitively and irreversibly inhibits DHF reductase. DHF reductase inhibition prevents the formation of THF (Choice D). After entering the target cell, MTX undergoes polyglutamation, which prevents the movement of MTX out of the cell, resulting in intracellular accumulation of MTX for later use. Similarly, folate and recycled DHF are stored within the cell via polyglutamation. Because MTX inhibits DHF reductase, folic acid and DHF polyglutamate will accumulate in cells. (Choice B) Folinic acid (leucovorin) is a reduced form of folic acid that can be used to counter the toxic effects of MTX chemotherapy. Folinic acid selectively "rescues" normal cells by competing with MTX for DHF reductase binding sites. It can reactivate DHF reductase, therefore allowing re-initiation of DNA synthesis. (Choice C) Para-aminobenzoic acid (PABA) is a folic acid precursor in prokaryotes. Sulfonamide antibiotics are chemical analogues of PABA that inhibit the enzyme dihydropteroate synthetase, preventing bacterial conversion of PABA to folic acid. Humans lack the ability to convert PABA to folic acid and require dietary folate. (Choice E) Thymidylic acid is a nucleotide that contributes to pyrimidine formation. Its synthesis is inhibited by MTX. Educational objective: Methotrexate is a folic acid antagonist used to treat ectopic pregnancy. It competitively inhibits the enzyme dihydrofolate (DHF) reductase, which catalyzes the synthesis of tetrahydrofolate. DHF reductase inhibition causes the intermediate DHF to accumulate intracellularly. __________ References: Methotrexate: the pharmacology behind medical treatment for ectopic pregnancy. (http://www.ncbi.nlm.nih.gov/pubmed/22510625) Low-dose methotrexate results in the selective accumulation of aminoimidazole carboxamide ribotide in an erythroblastoid cell line. (http://www.ncbi.nlm.nih.gov/pubmed/23887097)

A 23-Year-Old Woman Comes to the Emergency Department with Vaginal