Effects of β-lapachone, a peroxide-generating quinone, on macromolecule synthesis and degradation in Trypanosoma cruzi

Abstract

Incubation of Trypanosoma cruzi epimastigotes with β-lapachone (3,4-dihydro-2,2-dimethyl-2 H-naphtho[1,2- b]pyran-5,6-dione), a lipophilic o-quinone, produced inhibition of [ 3H]thymidine, [ 3H]uridine, and l-[ 3H]leucine incorporation into DNA, RNA, and protein, respectively. With 1.6 μ m β-lapachone, DNA synthesis was preferentially inhibited. The inhibition was irreversible, and time and concentration dependent. Other effects of β-lapachone were (a) inhibition of 3H precursor uptake into epimastigotes, (b) exaggerated degradation of DNA, RNA, and protein, (c) increased unscheduled synthesis of DNA, and (d) increased number of strand breaks in nuclear and kinetoplast DNA. DNA damage by 1.6 μ m β-lapachone was repaired by reincubating the drug-treated epimastigotes in fresh medium for 24 h, but with 7.8 μ m β-lapachone DNA damage was irreversible. The p-quinone isomer α-lapachone (3,4-dihydro-2,2-dimethyl-2 H-naphtho[2,3- b]pyran-5,10-dione), was less effective than β-lapachone, especially on DNA and RNA synthesis, and did not stimulate unscheduled DNA synthesis. Since β-lapachone redox cycling in T. cruzi generates oxygen radicals while α-lapachone does not (A. Boveris, R. Docampo, J. F. Turrens, and A. O. M. Stoppani (1978) Biochem. J. 175, 431–439) , the summarized results support the hypothesis that oxygen radicals contribute to β-lapachone toxicity in T. cruzi.