Enhancement of the mutagenicity of carcinogenic arylamines by ethinyl estradiol.
Ethinyl estradiol, the estrogenic component of oral contraceptives, has been shown to enhance the mutagenicity of 2-aminofluorene, 2-acetylaminofluorene, N-hydroxy-2-acetylaminofluorene, and N-acetoxy-2-acetylaminofluorene with strain TA 98 of Salmonella typhimurium and various rat liver activating systems. The magnitude of the enhancement of mutation produced by ethinyl estradiol is dependent upon: the type of mixed-function oxidase inducer of the liver activating system; the structure and concentration of the arylamine; the concentration of ethinyl estradiol; and metabolism of ethinyl estradiol to its catechol, 2-hydroxyethinyl estradiol, by the activating system. Moxestrol, a biologically potent estrogenic derivative of ethinyl estradiol which is not metabolized effectively to its catechol by the mixed-function oxidases, does not enhance the mutagenicity of the above arylamines and related compounds. Both 2-hydroxyethinyl estradiol and 2-hydroxymoxestrol enhance the mutagenicity of 2-aminofluorene and 2-acetylaminofluorene. Neither the estrogens nor their catechols are mutagenic by themselves in this system. In the presence of ethinyl estradiol, a marked inhibition of ring hydroxylation of 2-acetylaminofluorene was demonstrated. Since ring hydroxylation is a well established detoxification pathway of arylamine and arylamide metabolism, the enhancement of mutagenicity by ethinyl estradiol may be the result of a net increase in N-hydroxylation of arylamines and arylamides.
D015073:2-Acetylaminofluorene / Q000378:metabolism / Q000633:toxicity*; D000099:Acetoxyacetylaminofluorene / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens; D003043:Cocarcinogenesis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004997:Ethinyl Estradiol / Q000031:analogs & derivatives / Q000633:toxicity*; D005449:Fluorenes / Q000633:toxicity*; D006881:Hydroxyacetylaminofluorene / Q000633:toxicity; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced; D008656:Mestranol / Q000378:metabolism; D009153:Mutagens; D051381:Rats; D011919:Rats, Inbred Strains
D002273:Carcinogens; D005449:Fluorenes; D009153:Mutagens; C012177:2-aminofluorene; D004997:Ethinyl Estradiol; D006881:Hydroxyacetylaminofluorene; D000099:Acetoxyacetylaminofluorene; C011310:moxestrol; D015073:2-Acetylaminofluorene; D008656:Mestranol