Comparative toxicity and mutagenicity of N-hydroxy-2-acetylaminofluorene and 7-acetyl-N-hydroxy-2-acetylaminofluorene in human lymphoblasts.
Exponentially growing TK6 human lymphoblasts were exposed to either 0-50 microM N-hydroxy-2-acetylaminofluorene (N-OH-AAF) or 0-10 microM 7-acetyl-N-hydroxy-2-acetylaminofluorene (7-acetyl-N-OH-AAF) in both the absence and presence of a partially purified preparation of hamster-liver N-arylhydroxamic acid N,O-acyltransferase (AHAT). Neither N-arylhydroxamic acid was toxic to the lymphoblasts, nor mutagenic at the thymidine kinase (tk) locus, in the absence of AHAT over the concentration range examined. In the presence of AHAT, an enzyme that activates N-arylhydroxamic acids to electrophilic N-acetoxyarylamine intermediates, both compounds caused toxicity and mutagenicity in TK6 cells. The 7-acetyl-N-OH-AAF was approximately 10-fold more toxic and mutagenic than the unsubstituted N-OH-AAF. These data demonstrate that metabolism of these N-arylhydroxamic acids, presumably to N-acetoxyarylamine intermediates by AHAT, is a key event in the biological activity of these agents. In addition, the presence of electron-withdrawing 7-acetyl substituent that is thought to stabilize N-acetoxy intermediates, appears to enhance the biological activity of the unsubstituted N-OH-AAF.
Babson
J R
JR
Department of Pharmacology and Toxicology, College of Pharmacy, University of Rhode Island, Kingston 02881.
Gavitt
N E
NE
Boteju
L W
LW
Hanna
P E
PE
D000107:Acetylation; D000123:Acetyltransferases; D000217:Acyltransferases / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006881:Hydroxyacetylaminofluorene / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D013937:Thymidine Kinase / Q000235:genetics
D009153:Mutagens; D006881:Hydroxyacetylaminofluorene; D000217:Acyltransferases; D000123:Acetyltransferases; C019736:N-hydroxyarylamine O-acetyltransferase; D013937:Thymidine Kinase