Wistar (Cpb:WU), F344 or Sprague-Dawley rats were sequentially treated with cyproterone acetate (CA) for 21 days, testosterone propionate (TP) for 3 days, followed by a single i.v. injection of N-methyl-N-nitrosourea (MNU). One group of Wistar rats was castrated 4 weeks after MNU injection, and another group 58 weeks after MNU, when the first prostatic carcinoma was detected. Control groups received only CA + TP, CA, MNU, or they remained untreated. Early or late castration inhibited the development of atypical hyperplasia of the ventral prostate in Wistar rats. This lesion was induced by the CA + TP + MNU treatment in F344 rats, but not Sprague-Dawley rats; in Wistar rats, it was induced by CA + TP treatment, irrespective of whether MNU was given. Hypertrophic-hyperplastic lesions of the seminal vesicle were induced by MNU, irrespective of pretreatment, and their development was prevented by early castration and inhibited by late orchiectomy. Dorsolateral prostate carcinomas and preneoplasia occurred only in low incidence in Wistar and Sprague-Dawley rats. These lesions were absent in F344 rats that had received treatment with CA + TP + MNU. No dorsolateral prostate (pre)neoplasia was found in Wistar rats subjected to early orchiectomy, but rats castrated at 58 weeks had an incidence similar to that for the intact group treated with CA + TP + MNU. This finding supports the contention that androgens are required for the development of MNU-induced prostatic cancer in rats but that advanced carcinomas are androgen insensitive. Differences in incidence and localization of prostatic proliferative lesions between F344 and Wistar rats and between dorsolateral and ventral prostate could not be explained by differences in epithelial cell proliferative responses to CA + TP treatment at the time of MNU injection, since they were similar in ventral and dorsolateral prostate and were more prominent in F344 rats than in Wistar rats. DNA damage as estimated by MNU-induced unscheduled DNA synthesis also did not differ between dorsolateral and ventral prostate.
Laboratory models were used to study the inhibition of mutagen formation by Maillard-type reactions during cooking of meats or fish. The amino acid L-proline (L-pro) was an effective, dose-dependent inhibitor of the development of mutagenicity (Ames test) in a liquid-reflux model of glucose + glycine + creatine known to produce IQ-type mutagens (MeIQx and 7,8-DiMeIQx). L-pro also inhibited formation of mutagens in a reflux model of threonine + creatine, developed in our laboratory, which yields a novel class of IQ-"like" aminoimidazol-4-one mutagens. A mixture of L-pro and L-tryptophan (L-trp) at lower concentrations of each yielded increased inhibition, compared with the findings when each inhibitor was tested by itself.
The essential amino acid l‐tryptophan (l‐Trp) was found to be an effective inhibitor of the development of mutagenicity (Ames test) in liquid‐reflux models known to produce identified IQ‐type mutagens, such as 2‐amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline (MeIQx) and 2‐amino‐3,7,8‐trimethylimidazo[4,5‐f]qninoxaline (7,8‐DiMeIQx), and in reflux models recently developed in our laboratory that have been found to produce novel IQ‐“like” mutagens (aminoimidazol‐4‐ones), which we have identified as 2‐amino‐1‐methyl‐5‐propylideneimidazol‐4‐one (TCP‐1), and 2‐amino‐5‐ethylidene‐1‐methylimidazol‐4‐one (TCP‐2 or ACP). Selected indoles other than l‐Trp were also found to be effective inhibitors of mutagen formation in these same reflux models. A mechanism of inhibition of mutagen formation based on the preferential reaction of mutagen precursor aldehydes with the indole‐ring nitrogen of these inhibitors, rather than with creatinine, is indicated, and a new “concerted condensation model” for the formation of IQ‐type mutagens proposed.
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