Phenolphthalein and bisacodyl: assessment of genotoxic and carcinogenic responses in heterozygous p53 (+/-) mice and syrian hamster embryo (SHE) assay.
Phenolphthalein (800 and 2400 mg/kg/day by gavage and 2400 mg/kg/day by diet) and bisacodyl (800-500, 4000-2000, and 8000 mg/kg/day by gavage) were administered to 15 male and 15 female and 20 male and 20 female p53(+/-) mice respectively for 26 weeks to investigate the potential carcinogenicity of each compound. Toxicokinetic analyses confirmed systemic exposure. p-Cresidine was administered by gavage (400 mg/kg/day) and served as the positive control agent in each study. Dietary phenolphthalein reduced survival in both sexes and early deaths were attributed to thymic lymphoma. No bisacodyl-related neoplasms were observed. Regardless of route of administration to p53(+/-) mice, phenolphthalein but not bisacodyl was unequivocally genotoxic, causing increased micronuclei in polychromatic erythrocytes. In the Syrian hamster embryo (SHE) cell transformation assay, phenolphthalein caused increases in morphologically transformed colonies, thereby corroborating NTP's earlier reports, showing phenolophthalein has potential carcinogenic activity. Bisacodyl was negative in the SHE assay. Results of these experiments confirm an earlier demonstration that dietary phenolphthalein causes thymic lymphoma in p53(+/-) mice and show that (1) phenolphthalein causes qualitatively identical results in this transgenic model regardless of route of oral administration, (2) phenolphthalein shows evidence of micronucleus induction in p53(+/-) mice for up to 26 weeks, (3) phenolphthalein induced transformations in the in vitro SHE assay, and (4) bisacodyl in p53(+/-) mice induces neither drug-related neoplasm, nor micronuclei in polychromatic erythrocytes, and did not induce transformations in the in vitro SHE assay.
Stoll
R E
RE
Stoll & Associates, LLC, Storrs Mansfield, Connecticut 06268, USA. rstoll@prodigy.net
Blanchard
K T
KT
Stoltz
J H
JH
Majeska
J B
JB
Furst
S
S
Lilly
P D
PD
Mennear
J H
JH
D000818:Animals; D001726:Bisacodyl / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity; D002400:Cathartics / Q000493:pharmacokinetics / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D006224:Cricetinae; D005260:Female; D016158:Genes, p53; D008223:Lymphoma / Q000139:chemically induced / Q000473:pathology; D008297:Male; D008647:Mesocricetus / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*; D015162:Micronucleus Tests; D020113:Phenolphthalein / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D013953:Thymus Neoplasms / Q000139:chemically induced* / Q000473:pathology; D016159:Tumor Suppressor Protein p53
D002273:Carcinogens; D002400:Cathartics; D016159:Tumor Suppressor Protein p53; D001726:Bisacodyl; D020113:Phenolphthalein