Dihydrofolate reductase drugs that inhibit

Folate coenzyme concentrations may also decline as a result of treatment with drugs that inhibit dihydrofolate reductase, eg, methotrexate. 

The combined use of sulfonamides or sulfones with dihydrofolate reductase inhibitors, such as trimethoprim Bactrim, Septra) or pyrimethamine Fansidar), s, a good example of the synergistic possibilities that exist in multiple-drug chemotherapy. This type of impairment of the parasite s metabolism is termed sequential blockade. Using drugs that inhibit at two different points in the same biochemical pathway produces parasite lethality at lower drug concentrations than are possible when either drug is used alone. 

FOLATE DEFICIENCY Folate deficiency is a common complication of diseases of the small intestine, which interfere with the absorption of dietary folate and the recirculation of folate through the enterohepatic cycle. In acute or chronic alcohohsm, daily intake of dietary folate may be severely restricted, and the enterohepatic cycle of the vitamin may be impaired by toxic effects of alcohol on hepatic parenchymal cells this is the most common cause of folate-deficient megaloblastic erythropoiesis. However, it also is the most amenable to therapy, inasmuch as the reinstitution of a normal diet is sufficient to overcome the effect of alcohol. Disease states characterized by a high rate of cell turnover, such as hemolytic anemias, also may be complicated by folate deficiency. Additionally, drugs that inhibit dihydrofolate reductase (e.g., methotrexate and trimethoprim) or that interfere with the absorption and storage of folate in tissues (e.g., certain anticonvulsants and oral contraceptives) can lower the concentration of folate in plasma and may cause a megaloblastic anemia. 

Antineoplastic, immunosuppressant cell cycle-specific drug that inhibits dihydrofolate reductase. Major dose reduction required in renal impairment. Tox GI distress, myelosuppression, crystalluria. Leucovorin rescue used to reduce toxicity. 

Orally absorbed sulfa-type drug that inhibits dihydrofolate reductase used for treatment of urinaty tract infections caused by Cram-nega-lives often used with sulfamethoxazole. 

All of these compounds are inhibitors of dihydrofolate reductase in bacteria, plasmodia, and humans. Fortunately, they have a significantly high affinity for bacterial and protozoan dihydrofolate reductases. Pyrimethamine, for example, inhibits parasite dihydrofolate reductase at levels several hundred times lower than required to inhibit dihydrofolate reductase in humans. This is the basis of their selective toxicity. The selective toxicity can be increased upon supplying additional folic acid to the host organism, which the parasite cannot use. In fact, diaminopyrimidines (trimetoprim, pyrimethamine) were initially suggested as medicinal and preventative drugs against malarial infections. It was shown that all powerful inhibitors of dihydrofolate reductase can remove the malarial parasite with relatively minor consequences in the host. 

Pharmacology Leucovorin is one of several active, chemically reduced derivatives of folic acid. It is useful as an antidote to drugs that act as folic acid antagonists. Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. 

Other classes of proteins that have been clearly identified as drug receptors include enzymes, which may be inhibited (or, less commonly, activated) by binding a drug (eg, dihydrofolate reductase, the receptor for the antineoplastic drug methotrexate) ... 

Tetrahydrofolate cofactors participate in one-carbon transfer reactions. As described above in the section on vitamin B12, one of these essential reactions produces the dTMP needed for DNA synthesis. In this reaction, the enzyme thymidylate synthase catalyzes the transfer of the one-carbon unit of N 5,N 10-methylenetetrahydrofolate to deoxyuridine monophosphate (dUMP) to form dTMP (Figure 33-2, reaction 2). Unlike all of the other enzymatic reactions that utilize folate cofactors, in this reaction the cofactor is oxidized to dihydrofolate, and for each mole of dTMP produced, one mole of tetrahydrofolate is consumed. In rapidly proliferating tissues, considerable amounts of tetrahydrofolate can be consumed in this reaction, and continued DNA synthesis requires continued regeneration of tetrahydrofolate by reduction of dihydrofolate, catalyzed by the enzyme dihydrofolate reductase. The tetrahydrofolate thus produced can then reform the cofactor N 5,N 10-methylenetetrahydrofolate by the action of serine transhydroxy- methylase and thus allow for the continued synthesis of dTMP. The combined catalytic activities of dTMP synthase, dihydrofolate reductase, and serine transhydroxymethylase are often referred to as the dTMP synthesis cycle. Enzymes in the dTMP cycle are the targets of two anticancer drugs methotrexate inhibits dihydrofolate reductase, and a metabolite of 5-fluorouracil inhibits thymidylate synthase (see Chapter 55 Cancer Chemotherapy). 

Folic acid deficiency can be caused by drugs that interfere with folate absorption or metabolism. Phenytoin, some other anticonvulsants, oral contraceptives, and isoniazid can cause folic acid deficiency by interfering with folic acid absorption. Other drugs such as methotrexate and, to a lesser extent, trimethoprim and pyrimethamine, inhibit dihydrofolate reductase and may result in a deficiency of folate cofactors and ultimately in megaloblastic anemia. 

A drug receptor is a specialized target macromolecule, present on the cell surface or intracellularly, that binds a drug and mediates its pharmacologic actions. Drugs may interact with enzymes (for example, inhibition of dihydrofolate reductase by trimethoprim, p. 294),... 

The active form of folate is the tetrahydro-derivative that is formed through reduction by dihydrofolate reductase. This enzymatic reaction (Figure 29.5) is inhibited by trimethoprim, leading to a decrease in the folate coenzymes for purine, pyrimidine, and amino acid synthesis. Bacterial reductase has a much stronger affinity for trimethoprim than does the mammalian enzyme, which accounts for the drug s selective toxicity. [Note Examples of other folate reductase inhibitors include pyrimethamine, which is used with sulfonamides in parasitic infections (see p. 353), and methotrexate, which is used in cancer chemotherapy (see p. 378).]... 

Correct answer = C. Trimethoprim is 20 to 50 times more potent than sulfamethoxazole. It inhibits the enzyme dihydrofolate reductase, thus preventing both purine and pyrimidine synthesis. Trimethoprim resistance has been observed in gram-negative bacteria caused by the presence of a plasmid that codes for an altered dihydrofolate reductase with a lower affinity for the drug. 

In addition to the examples discussed above, the structures of many clinically and biologically important proteins have been determined. Some of these are amenable to immediate use in drug discovery efforts. These include enzymes such as dihydrofolate reductase (Jansy, 1988), and thymidilate synthase (Appelt et al, 1991) both of which are involved in the synthesis of DNA precursors. Their inhibition is a target in anticancer chemotherapies. Structures of other proteins such as cAMP-dependent protein kinase, acetylcholinesterase, and the glucocorticoid receptor add to the knowledge base that will open new avenues... 

A classic example of a drug that works by species-specific protein inhibition is trimethoprim (TMP). Because this drug binds to bacterial dihydrofolate reductase (DHFR) 10 moie tightly than to the mammalian enzyme, there is a therapeutic concentration in which the drug can be used as an antibacterial with little deleterious consequences for a mammalian host. 

Methotrexate, for example, a folic acid antagonist, competitively inhibits dihydrofolate reductase, preventing the synthesis of tetrahydrofolic acid (the coenzyme that is important in synthesis of amino and nucleic acids). This drug also provides a cogent illustration of the need to exploit every possible... 

The recommendations for the treatment of EPM using pyrimethamine, trimethoprim and sulfadiazine were originally based on the use of these drugs for the treatment of malaria and toxoplasmosis in humans. Either pyrimethanune or trimethoprim in combination with sulfadiazine or sulfamethoxazole have been used with some success and have gained widespread acceptance as the treatment of choice for EPM. Pyrimethamine and trimethoprim are diaminopyrimidine antimicrobial agents that inhibit dihydrofolate reductase (DHFR see Ch. 2). These agents interfere with... 

In the 1990s, it was found that tylophorine alkaloids inhibit several key targets for clinically important anticancer drugs, including the metabolic enzymes thymidylate synthase (TS) and dihydrofolate reductase [8, 94], TS catalyzes the reductive methylation of the substrate dUMP (2 -deoxyuridine 5 -monophosphate) to dTMP (2 -deoxythymidine 5 -monophosphate thymidylate) with concomitant conversion of the cofactor CH2THF (5,10-methylenetetrahydrofolate) to DHF (7,8-dihydrofolate) (see Equation 1). 

Pyrimethamine and proguanil are used as oral antimalarials.and inhibit the utilization of folate by the malarial parasite, so are valuable in chemoprophylaxis and in preventing the transmission of malaria. (See ANTIMALARIALS.) Trimethoprim is a useful antibacterial, and as an antiprotozoal in antimalarial therapy. The selectivity of these agents derives, in part, from the fact that whereas mammals can obtain folic acid from the diet, bacteria and the asexual forms of the malarial parasite must synthesize it. Also, the dihydrofolate reductase enzyme in humans is less sensitive to these drugs than that of the parasites. 

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