Comparative mutagenicity testing of bropirimine, 2. Further characterization and mechanistic investigation of clastogenesis.
Bropirimine is an immunomodulator and has been investigated as an antineoplastic drug as well as for antiviral indications. However, the standard of prudence and the level of concern necessary in safety assessment in the alternative therapeutic situations, namely, antineoplastic therapy as opposed to treatment of non-life-threatening viral illnesses, is dramatically different. In previous reports from this laboratory, bropirimine was shown to be non-mutagenic in the Ames Salmonella assay (Aaron et al., 1989b), the in vitro UDS assay (Aaron et al., 1989a) and the L5178Y TK+/- assay but positive in the CHO cell chromosome aberration assay, in the presence of S9 (Aaron et al., 1991a). In this manuscript, we provide data gathered in attempts to further characterize the apparent requirement for S9 and understand the mechanism by which bropirimine induces chromosome aberrations. For example, heat inactivation of the S9 significantly reduced, but did not eliminate, the aberration induction. In addition, collection of mitotic cells without use of colcemid failed to reduce the aberration yield. Furthermore, no evidence of S9-mediated activation of bropirimine to an electrophilic, macromolecular binding species was observed in vitro, nor did lysosomal toxicity appear to contribute to the effect. Several analogs were tested for clastogenic potential; the 5-chloro analog was also clastogenic, but not the 5-iodo-, 5-bromo-3-fluorophenyl- or non-halogenated analogs. Thus, the mechanism of aberration induction remains obscure, but we have confirmed the need for presence of exogenous protein in order for the clastogenicity of bropirimine to be manifest and have ruled out several non-threshold mechanisms for toxicity.
Petry
T W
TW
Upjohn Company, Kalamazoo, MI 49001.
Aaron
C S
CS
Ulrich
R G
RG
Donarski
W J
WJ
Thilagar
A
A
Kumaroo
P V
PV
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity*; D001711:Biotransformation; D002460:Cell Line; D002869:Chromosome Aberrations; D006224:Cricetinae; D003412:Cricetulus; D003520:Cyclophosphamide / Q000494:pharmacology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D004247:DNA / Q000378:metabolism; D003703:Demecolcine / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D007093:Imidazoles; D009153:Mutagens; D008748:Methylcholanthrene; D003596:Cytosine; D003520:Cyclophosphamide; D004247:DNA; C033560:bropirimine; C002822:1-dodecylimidazole; D003703:Demecolcine