Trimethoprim, selective toxicity

Trimethoprim is a competitive inhibitor of the enzyme dihydrofolate reductase and can thus prevent the formation of tetrahydrofolate thereby blocking the synthesis of purines. The affinity of trimethoprim for the enzyme in microorganisms is 10,000 times higher than for the human enzyme which explains the selective toxicity. Used alone its main indication is acute uncomplicated urinary tract infections. It is then as effective as co-trimoxazole but has the advantage of fewer adverse reactions. 

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).]... 

Pyrimethamine and trimethoprim reversibly inhibit the second step in the synthesis of folic acid by inhibiting the enzyme dihydrofolate reductase, which catalyzes the reduction of dihydrofolic acid to tetrahydrofolic acid. The trimethoprim-binding affinity is much stronger for the bacterial enzyme than the corresponding mammalian enzyme, which produces selective toxicity. A powerful synergism exists between either pyrimethamine or trimethoprim and sulfonamides (e g., sulfemethoxazole and trimethoprim) because of sequential blockage of the same biosynthetic pathway. 

Trimethoprim (hotiom left) acts on the same metabolic pathway as sulphonamides, but is an inhibitor of dihydrofolaie reductase (CD), h is selectively toxic because its affinity for the bacterial enzyme is 50 (KK)... 

It is evident, therefore, that the 2,4-diaminopyrimidines, like pyrimethamine and trimethoprim, the dihydrotriazines like proguanil (in its active metabolite form), the 2,4-diaminopteridines, and methotrexate, inhibit dihydrofolate reductase. Their selective toxicity to plasmodia may be due to a combination of greater binding to the parasite enzyme and to their selective uptake by parasitised erythrocytes. However, a new antifolic mode of action has recently been proposed for compounds like tetrahydrohomopteroic acid [288], which may inhibit folate metabolism by an action on the feedback... 

Shoaf S E. Schwark W S, Guard C L 1989 Pharmacokinetics of sulfadiazine/trimethoprim in neonatal male calves effect of age and penetration into cerebrospinal fluid. American Journal of Veterinary Research 50 396-402 Taylor W M, Simpson C F, Martin F G 1972 Certain aspects of toxicity of an amicarbalide formulation to ponies. American Journal of Veterinary Research 33 533-541 Watkins W M, Mosobo M 1993 Treatment of Plasmodium falciparium malaria with pyrimethamine and sulphadoxine a selective pressure for resistance is a function of long elimination half-life. Transactions of the Royal Society of Tropical Medicine and Hygiene 87 75-79... 

Inhibition of folic acid synthesis in susceptible microorganisms and ultimately the synthesis of nucleic acids. By competing with para-aminobenzoic acid (PABA) for the enzyme dihydropteroate synthetase, sulphonamides prevent the incorporation of PABA into dihydrofolate, while trimethoprin, by selectively inhibiting dihydrofolate reductase, prevents the reduction of dihydrofolate to tetrahydrofolate (folic acid). Animal cells, unlike bacteria, utilize exogenous sources of folic acid. Pyrimethamine inhibits protozoal dihydrofolate reductase, but is less selective for the microbial enzyme and therefore more toxic than trimethoprim to mammalian species. 

Pyrimethamine and trimethoprim are inhibitors of both bacterial and protozoal dihydrofolate reductase (DHFR) enzymes but do not affect the mammalian enzyme. Further specificity is achieved by the use of PABA antagonists, since they are competitive inhibitors of the protozoal dihydropteroate (DHP) synthase reaction, which condenses PABA with hydroxymethyldihydropteridine to form DHP, an intermediate in the tetrahydrofolate (THF) biosynthetic pathway. Protozoa synthesize THF de novo whereas humans require dietary folate. For this reason sulfur drugs are selective and virtually non-toxic to humans. 

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