Glucuronidation of carcinogenic arylamine metabolites by rat liver microsomes.
Since 2-acetylaminofluorene (2-AAF), 4-acetylaminobiphenyl (4-AABP) and 2-aminonaphthalene (2-AN) display varying degrees of carcinogenicity in the rat, which is capable of N-acetylating arylamines, an attempt was made to correlate the difference in carcinogenicity of these compounds with the ease of O-glucuronidation of their hydroxamic acids by rat hepatic microsomes, a reaction believed to be a detoxification mechanism. UDP-glucuronosyltransferase activity of rat hepatic microsomes was activated by Triton X-100. Glucuronidation by Triton X-100 activated microsomes of the N-hydroxy derivative of 2-AN was approximately 1.5 and 1.8 times faster than the corresponding derivatives of 2-aminofluorene (2-AF) and 4-aminobiphenyl (4-ABP) respectively. However, glucuronidation of the N-hydroxy-N-acetyl derivative of 2-AN was 40 and 17 times faster than the corresponding derivatives of 2-AF and 4-ABP respectively. Aroclor 1254 and 3-methylcholanthrene, but not phenobarbital, acetanilide and butylated hydroxytoluene, induced the enzyme for the glucuronidation of 2-AN derivatives. The present study (1) demonstrates an inverse relationship between the carcinogenicity of 2-AN, 4-AABP and 2-AAF and the ease of glucuronidation of their hydroxamic acid derivatives, and (2) suggests that, in addition to N- and C-hydroxylation, glucuronidation may play an important role in determining the carcinogenicity of arylamines and arylacetamides in the rat.
D015073:2-Acetylaminofluorene / Q000378:metabolism; D015081:2-Naphthylamine / Q000378:metabolism; D000611:Aminobiphenyl Compounds / Q000378:metabolism; D000818:Animals; D002084:Butylated Hydroxytoluene / Q000494:pharmacology; D002273:Carcinogens / Q000378:metabolism*; D005260:Female; D005965:Glucuronates / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000032:analysis / Q000096:biosynthesis; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism*; D017830:Octoxynol; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D005965:Glucuronates; D002084:Butylated Hydroxytoluene; D011092:Polyethylene Glycols; D017830:Octoxynol; D015073:2-Acetylaminofluorene; D015081:2-Naphthylamine; D014453:Glucuronosyltransferase; C020853:4-acetylaminobiphenyl