Homologous recombination induced by doxazosin mesylate and saw palmetto in the Drosophila wing‐spot test

Abstract

Benign prostatic hyperplasia (BPH) is the most common tumor in men over 40 years of age. Acute urinary retention (AUR) is regarded as the most serious hazard of untreated BPH. α-Blockers, such as doxazosin mesylate, and 5-α reductase inhibitors, such as finasteride, are frequently used because they decrease both AUR and the need for BPH-related surgery. An extract of the fruit from American saw palmetto plant has also been used as an alternative treatment for BPH. The paucity of information available concerning the genotoxic action of these compounds led us to assess their activity as inducers of different types of DNA lesions using the somatic mutation and recombination test in Drosophila melanogaster. Finasteride did not induce gene mutation, chromosomal mutation or mitotic recombination, which means it was nongenotoxic in our experimental conditions. On the other hand, doxazosin mesylate and saw palmetto induced significant increases in spot frequencies in trans-heterozygous flies. In order to establish the actual role played by mitotic recombination and by mutation in the genotoxicity observed, the balancer-heterozygous flies were also analyzed, showing no increment in the total spot frequencies in relation to the negative control, for both drugs. Doxazosin mesylate and saw palmetto were classified as specific inducers of homologous recombination in Drosophila proliferative cells, an event linked to the loss of heterozygosity.

Identification of Mutagenic Aromatic Amines in River Samples with Industrial Wastewater Impact

“…6,7-Dimethoxy-2-(1-piperazinyl)-4-quinazolinamine did not show any activity in the tested concentration range (0.006−20 ng/μL medium). However, the parent compound doxazosine has been shown to induce genotoxic effects in the homologous recombination mechanism of DNA 39 although it has been reported as inactive in the Ames test with strain TA98 and TA100 with and without metabolic activation. 41 The correlation of the peak area of the doxazosine transformation product with mutagenicity together with literature findings suggests that the metabolite might contribute to the activity via a comutagenicity mechanism in the presence of other promutagens, which might be of relevance for aromatic amines as shown recently.…”

“…These compounds include four industrial chemicals, 4-dimethylaminopyridine, 3-formylindole, and 2,3- and 2,8-phenazinediamine ; three amino acids, phenylalanine, tyrosine, and tryptophan, which are also used as nutritional supplements; two pharmaceutical precursors, 2- and 4-hydroxyquinoline ; two pharmaceuticals, propranolol and telmisartan ; the metabolite of the pharmaceutical doxazosine 6,7-dimethoxy-2-(1-piperazinyl)-4-quinazolinamine ; the nucleobase guanine ; and the natural antioxidant L-ergothioneine , which is frequently used in personal care products. Doxazosine , used to treat acute urinary retention in benign enlargement of prostate, was tentatively identified (level 2 according to Schymanski et al) by a comparison with the MassBank spectrum. Compounds were detected in all six extracts except for 2,3-phenazinediamine and 2-hydroxyquinoline which were detected in four extracts.…”

Drosophila Accessory Gland: A Complementary In Vivo Model to Bring New Insight to Prostate Cancer

“…It was illustrated in a study where Drosophila was used as the in vivo tumorigenesis model to confirm the effects of radiosensitizing compounds that were screened initially in vitro in DU145 cells, with exploitation of the eye phenotype to evaluate the drug toxicity and effect on tumorigenesis [120]. Genotoxicity can also be done during Drosophila wing disc development using the fast SMART (somatic mutation and recombination test), as it was used to evaluate potential risks induced by molecules used in the treatment of benign prostate hyperplasia [121].…”