Several compounds used clinically in drug abuse therapy were evaluated for genetic activity in a series of in vivo and in vitro assays. The second report in this series describes the results for one of these compounds, Methadone. A previous report described the results for Naltrexone. Methadone is a synthetic narcotic analgesic used as a substitute for Heroin in drug detoxification programs. Methadone demonstrated weak activity in the E. coli DNa repair system and in the Neurospora crassa and the mouse lymphoma forward-mutation assays under the conditions of this evaluation. Additional analysis of the ad-3 mutants induced by a related compound, LAAM, in Neurospora indicated that they were the result of a parasexual phenomena rather than forward mutation. Therefore, the methadone-induced ad-3 mutants also may be due to a parasexual phenomena.

Several compounds used clinically in drug abuse therapy were evaluated for genetic activity in a series of in vivo and in vitro assays. This third report in the series describes the results for one of these compounds, LAAM (L-alpha-acetyl methadol). Previous reports described results from a three phase testing program for Naltrexone and Methadone. LAAM is related chemically to the narcotic analgesic oxymorphine, and is related chemically to a narcotic antagonist, naloxone. LAAM exhibited genetic activity in the ad-3 forward-mutation test in Neurospora crassa and also was weakly mutagenic in the mouse lymphoma forward-mutation assay. Further analysis of the ad-3 mutants from N. crassa indicated that they were the result of a parasexual phenomenon rather than forward mutation. There was one confirmed translocation carrier in the heritable translocation study, which by conservative interpretation might imply some germ-cell risk associated with exposure to LAAM.

Several compounds used clinically in drug abuse therapy were evaluated for genetic activity in a series of in vitro assays. initial report describes the results for one of these compounds, Naltrexone. Nal trexone is a relatively nontoxic drug antagonist related to Naloxone which appears to be effective in diminishing the euphoria and dependence upon heroin in clinical studies. With the exception of weak nonspecific DNA damage observed in an g. coli DNA repair test and possibly with WI-38 cells as well, Naltrexone did not demonstrate significant potential for the i nduction of gene mutations or chromosomal aberrations under the conditions of this evaluation.

Several compounds used clinically in drug abuse therapy were evaluated for genetic activity in a series of in vitro assays. This initial report describes the results for one of these compounds, Naltrexone. Nalrexone is a relatively nontoxic drug antagonist related to Naloxone which appears to be effective in diminishing the euphoria and dependence upon heroin in clinical studies. With the exception of weak nonspecific DNA damage observed in an E. coli DNA repair test and possibly with WI-38 cells as well, Naltrexone did not demonstrate significant potential for the induction of gene mutations or chromosomal aberrations under the conditions of this evaluation.

In vivo somatic chromosome mutation tests are usually carried out using the bone marrow micronucleus test in the mouse. This test is also considered predictive for the study of clastogenic effects in germ cells. However, it has been reported that the sensitivity of the bone marrow micronucleus test is insufficient to detect unstable compounds or short-lived metabolites and the use of target cells with metabolic activity (hepatocytes) has been questioned. In order to analyze in vivo micronucleus induction in cells with metabolic enzyme activity, we compared the sensitivity of somatic and germ cells to four carcinogens in the bone marrow and spermatid micronucleus test in the mouse. Three procarcinogens with a complex metabolic pattern (dimethylnitrosamine, diethylnitrosamine and 1,1-dimethylhydrazine) and one direct unstable mutagen (β-propiolactone) were tested. All four carcinogens were not detected by the bone marrow micronucleus test but were detected in the mouse spermatid micronucleus test in which they induced clear clastogenic effects, as was the case in a previous study in liver micronucleus test. In conclusion, this study demonstrates that the bone marrow micronucleus test is not sufficient for the prediction of a clastogenic hazard in germ cells. In addition to a second in vivo test in an organ with metabolic enzymes, i.e., the liver, the spermatid micronucleus test can be performed when a specific risk to the testis is likely.