Comparative mutagenicity testing of bropirimine, 3. Bropirimine does not induce cytogenetic damage in vivo in the rat but does produce micronuclei in the mouse.
Bropirimine is a biological response modifier (BRM) with potential antineoplastic and antiviral indications. Recent results have documented the negative findings in the Ames Salmonella assay, the in vitro UDS assay and the mouse lymphoma TK+/- assay as well as positive findings in the in vitro cytogenetic assay in CHO cells. Extensive mechanistic studies failed to establish the reason for positive findings in the in vitro cytogenetic assays. The data reported here cast doubt on the relevance of the in vitro cytogenetic results and suggest limited in vivo genotoxic potential. At doses as high as 150 mg/kg (i.p.) and 6.73 g/kg (p.o.), no evidence of chromosome aberration induction was observed in rat bone marrow cytogenetic assays. Consistent with these data, plasma and bone marrow tissue levels in similarly treated animals were well below those required for activity in the in vitro chromosome aberration assays. Positive results were obtained in the mouse micronucleus assay. However, the significance of these findings may be explained by markedly different pathways of metabolism in that species as compared to the rat. Hence, the findings in the mouse are of questionable relevance to human risk assessment. Exposure of humans to bropirimine, under therapeutically acceptable regimens is unlikely to constitute a genotoxic health hazard.
Aaron
C S
CS
Upjohn Company, Kalamazoo, MI 49001.
Petry
T W
TW
Branstetter
D G
DG
Wickrema-Sinha
A J
AJ
Yu
R
R
Sorg
R
R
Thilagar
A
A
Kumaroo
P V
PV
Sams
J P
JP
Thornburg
B A
BA
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002851:Chromatography, High Pressure Liquid; D002869:Chromosome Aberrations; D003520:Cyclophosphamide / Q000494:pharmacology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000097:blood / Q000633:toxicity / Q000652:urine; D005260:Female; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009153:Mutagens; D051381:Rats; D011919:Rats, Inbred Strains
D000970:Antineoplastic Agents; D009153:Mutagens; D003596:Cytosine; D003520:Cyclophosphamide; C033560:bropirimine