The effects of deuterium and methyl substitution on DBCP-induced testicular toxicity and DNA damage

226 the nitroimidazoarenes (NIAs). NIAs are derived from the AIAs by the substitution of the nitro for the amino group. Attempts to oxidize the AIAs directly to the NIAs were unsuccessful. The NIAs were synthesized by the diazotization of the AIAs and reaction with nitrite. They were characterized by TLC, NMR and mass spectra. 8 NIAs were obtained and their mutagenic activities were assayed by means of the Salmonella typhimurium strains TA98, TA98NR (deficient in a nitroreductase) and TA98/1,8-DNP 6 (deficient in an Oacetyltransferase). In analogy to carbocyclic nitroarenes the NIAs proved mutagenic in absence of an exogenous activation system. The mutagenic potencies of the NIAs in TA98 paralleled closely those of the matching AIAs; nitro-IQ, e.g., inducing 80,000 rev./nmole was equally mutagenic as IQ (in presence of rat liver microsomes). The mutagenic potency of nitro-IQ was unaffected by the loss of the nitroreductase. However, it was severely reduced in the strain lacking the acetyltransferase. In conclusion, the parallel structure-activity relationships of the NIAs and AIAs suggest an essential similarity of their mechanisms of mutagenesis. This similarity is explained by the occurrence of a common metabolite, the hydroxylamine which is generated by extracellular, microsomal oxidation of the AIAs and by intracellular reduction of the NIAs. It is further concluded that the higher or lower mutagenic activities of individual NIA/AIA pairs are not controlled at the stage of nitroreduction or N-hydroxylation.

57 Soderlund, E.J., G. Brunborg, J.G. Omichinski, J.A. Holme, J.E. Dahl, S.D. Nelson and E. Dybing, Department of Toxicology, National Institute of Public Health, Oslo (Norway), and Department of Medicinal Chemistry, University of Washington, Seattle, WA (U.S.A.) The effects of deuterium and methyl substitution on DBCP-induced testicular toxicity and DNA damage

Occupational exposure to the nematocide 1,2dibromo-3-chloropropane (DBCP) has caused

oligospermia, azoospermia and sterility in chemical plant workers and applicators. Furthermore, doses of DBCP which produce acute testicular toxicity in rats are capable of causing testicular DNA damage as determined by alkaline ehition. Earlier studies with selectively methylated analogs of DBCP provided strong evidence that there was a poor correlation between the effects of deuterium/methylation on nephrotoxicity versus mutagenicity in the Salmonella test. In the present study, these same deuterated/methylated analogs were used to determine wether the mechanism(s) of DBCP-induced testicular necrosis and DNA damage mimicked either its mechanism of mutagenicity or its mechanism of nephrotoxicity. At 340 /~moles/kg all of the deuterated analogs caused similar degrees of testicular necrosis and atrophy as the parent compound. Furthermore, the perdeutero analog increased the rate of alkaline elution of testicular DNA in a dose-dependent fashion to at least the same degree as nondeuterated DBCP. From experiments with the selectively methylated analogs, it was found that the C3-methyl compound, but not the Cl-methyl analog, was capable of causing either testicular necrosis or testicular DNA damage. Based on these results, it appears that the mechanism of in vivo DBCP-induced testicular DNA damage and testicular necrosis resembles the mechanism of nephrotoxicity and is different from the mechanism of DBCP-induced mutagenicity in vitro.

58 Benigni, R., Istituto Superiore di Sanit~t, Rome (Italy) REPAD, a new pattern recognition method for structure-activity studies

The biological activity of structurally similar substances (congeneric) can be a regular and well-behaved function of structurally related parameters. On the other hand, any drastic change in structure may result in discontinuity of the structure-activity relationship, and the activity of non-congeneric compounds will be not predictable. The traditional linear regression methods used for the so-called "Hansch approach" are