Induction of lacI mutations in Big Blue rats treated with tamoxifen and alpha-hydroxytamoxifen.
The antiestrogen tamoxifen is carcinogenic in the liver and uterus of rats. Liver tumors appear to result from sequential hydroxylation and esterification of the alpha-carbon of tamoxifen followed by DNA adduct formation. The mechanism for the induction of uterine tumors is not known. Big Blue rats were treated by intraperitoneal injection with 21 daily doses of 54 micromol/kg tamoxifen or its proximate carcinogenic metabolite alpha-hydroxytamoxifen. One month after the last treatment, the mutant frequency in the lacI transgene was determined in the liver and uterus. For comparison, the mutant frequency in the hypoxanthine phosphoribosyl transferase (Hprt) gene of spleen lymphocytes was also measured. In the liver, tamoxifen (32+/-18 mutants/10(6) plaques; mean+/-SD) and alpha-hydroxytamoxifen (770+/-270 mutants/10(6) plaques) caused a significant increase in the mutant frequency of the lacI gene compared to solvent treated controls (10+/-10 mutants/10(6) plaques). 32P-Postlabeling analyses of liver DNA indicated three DNA adducts, one each from tamoxifen, N-desmethyltamoxifen, and N,N-didesmethyltamoxifen. Neither tamoxifen nor alpha-hydroxytamoxifen caused an increase in the mutant frequency in the lacI gene of the uterus or in the Hprt gene of spleen lymphocytes. These results suggest that induction of endometrial tumors in rats is not due to the genotoxicity of tamoxifen.
Gamboa da Costa
Gonçalo
G
Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, Av. Rovisco Pais, Lisboa 1049-001, Portugal.
Manjanatha
Mugimane G
MG
Marques
M Matilde
MM
Beland
Frederick A
FA
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D001835:Body Weight / Q000187:drug effects; D018736:DNA Adducts / Q000378:metabolism; D029968:Escherichia coli Proteins; D005260:Female; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D056968:Lac Repressors; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D009153:Mutagens; D009154:Mutation; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013997:Time Factors; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
D018931:Antineoplastic Agents, Hormonal; D001426:Bacterial Proteins; D018736:DNA Adducts; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D009153:Mutagens; D012097:Repressor Proteins; C110902:alpha-hydroxytamoxifen; D013629:Tamoxifen; D007041:Hypoxanthine Phosphoribosyltransferase