[Estimation of potential mutagenic activity of 24-epibrassinolide]. / Otsenka potentsial'noi mutagennoi aktivnosti 24-épibrassinolida.

Genotoxic effect of synthetic phytohormone analogue of steroid origin epibrassinolide was studied in in vitro- and in vivo-tests. Epibrassinolide did not display mutagenic properties in Ames' test (S. typhimurium, TA100) and DNA damaging activity test (DNA of phage lambda). The rise in the level of polichromatophilous erythrocytes with micronuclei was observed in the micronuclear test at intraperitoneal epibrassinolide injection at the dose of 500 mg/kg that seems to be associated with disturbance of cell membrane permeability.

Action of brassinosteroids in the cotton leafworm Spodoptera littoralis.

The two native plant hormones 24-epibrassinolide and 24-epicastasterone showed 50% competition for binding at IC(50) of 1-3.6 microM with [(3)H]ponasterone A using cultured imaginal wing discs from last-instar larvae of the cotton leafworm, Spodoptera littoralis (Boisduval) (Lepidoptera: Noctuidae). However, culture of imaginal wing discs in different concentrations of brassinosteroids, even up to 100 microM, demonstrated no induction of evagination. In contrast, 20E and the non-steroidal agonist RH-5992 competed respectively about 23- and 42-fold more effectively with labeled ponasterone A, and their ability (EC(50)) to induce disc evagination in vitro was 158 and 87 nM, respectively. Injection of 10 microg of brassinosteroids in newly-moulted last-instar larvae did not cause mortality above controls; higher mortalities were scored when brassinosteroids were injected late in the last instar.

Mutagenic activity of oxathiolane steroids: structural requirement for the genotoxic activity in Salmonella and E. coli.

Oxathiolanes and disulfonyl derivatives of steroids were tested for mutagenic activity in the Ames tester strains. The test compounds exhibited mutagenic activity without metabolic activation although metabolic activation markedly enhanced their activity. A significant decrease in the survival of the radiation-sensitive mutants recA, lexA and rer of E. coli was observed as compared to their wild-type counterpart in the presence of the test steroid. Structural features which appear to be crucial for the mutagenic activity in these steroidal drugs are: (i) an electron-donating group at position 3, and (ii) a bulky group anchored at the 5th and 6th positions. The test steroids appear to damage DNA which in turn initiates the SOS repair with the concomitant induction of mutation.

External genitalia abnormalities in male rats exposed in utero to finasteride, a 5 alpha-reductase inhibitor.

A series of studies was conducted to determine the developmental toxicity of the 5 alpha-reductase inhibitor finasteride (MK-0906) in rats. This compound was administered orally once daily to pregnant rats during various extended treatment periods during gestation. F1 offspring were evaluated on Day 20 of gestation as well as postnatally through mating to produce an F2 generation. MK-0906 treatment induced dosage-related incidences of hypospadias (penischisis) in male offspring with a threshold dosage level near 0.1 mg/kg/day and a 100% effect level of 100 mg/kg/day (with dosing through Day 20 of gestation). MK-0906 also caused decreased anogenital distance in male offspring. The dosage response for this effect (ranging from a 4.2% decrease at 0.003 mg/kg/day to a 38% decrease at 100 mg/kg/day) was more shallow than that for hypospadias. The decreases in anogenital distance were at least partially reversible postnatally with essentially complete recovery at dosages up to 0.1 mg/kg/day. There was also a dosage-related, temporary induction of nipples in F1 males. All of these effects were apparent following treatment on Days 6 through 17 of gestation but were more pronounced when dosing extended to Day 20 of gestation. Slight maternal toxicity consisting of minor decreases in body weight gain occurred only at dosages of 3 mg/kg/day and higher, indicating the selective nature of the developmental toxicity. The 5 alpha-reductase enzyme located in the rat fetal genital tubercle was studied in vitro and compared to that in the adult ventral prostate. The values for Km, Vmax, and IC50 for inhibition by MK-0906 were similar in the two tissues, suggesting that the enzymatic proteins in the genital tubercle and ventral prostate may be similar.

Synthesis of a new nor-aza-steroidal ester of p-N,N-bis-(2-chloroethyl)aminophenylbutyric acid and in vitro study of its mutagenicity and clastogenicity.

A new nor-aza-steroidal ester of chlorambucil has been synthesized. The study of the mitotic index in CHO and HeLa cells treated with this compound showed that it may be a cytostatic drug. It was also found that treatment of CHO cells with a dose as low as 5 micrograms/ml induces a large number of sister chromatid exchanges. A great number of abnormal metaphases has been observed when CHO cells were treated with the compound at a dose of 25 micrograms/ml. When the compound was tested in the Ames/Salmonella microsome assay, it was found to be mutagenic in strains TA100 and TA1535, both with and without metabolic activation.