Toxicity of the heterocyclic amine batracylin: investigation of rodent N-acetyltransferase activity and potential contribution of cytochrome P450 3A.
The heterocyclic amine, batracylin (BAT), is genotoxic and several lines of evidence suggest that acetylation is one step in the formation of a DNA-damaging product. The variation in susceptibility to BAT toxicity observed between rats and mice has also been linked to the acetylated product. BAT N-acetyltransferase (NAT) activity was determined in rat and mouse hepatic cytosols. Formation of acetylbatracylin (ABAT) was 6 times greater in F-344 hepatic samples compared to either mouse strain, while hepatic BAT NAT activities were similar in C57B1/6 and A/J mice. No deacetylation of ABAT was detected. In contrast, 2-aminofluorene NAT activity in C57B1/6 hepatic cytosol was twice that of the A/J strain and activities in both strains of mice were greater than in rat. Deacetylation of 2-acetylaminofluorene was detected in both species with enzyme activities in C57B1/6>A/J>F-344. Hepatocytes from the F-344 rats, the species most sensitive to BAT toxicity, were used to investigate the contribution of other biotransformation reactions to BAT cytotoxicity. Leakage of cellular lactate dehydrogenase was greater in hepatocytes from male rats than from females, increased on in vivo exposure to dexamethasone, and decreased in the presence of troleandomycin, suggesting that CYP3A-mediated biotransformation of BAT is involved in the formation of a cytotoxic product. When phenol red, a substrate for UDP-glucuronsyltransferase (UDPGT), was absent from the medium, BAT cytotoxicity was reduced. These data are consistent with a role for NAT, CYP, and UDPGT in the biotransformation of BAT.
Stevens
G J
GJ
University of Arizona, Tucson, USA.
Burkey
J L
JL
McQueen
C A
CA
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D011799:Quinazolines / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity
D009153:Mutagens; D011799:Quinazolines; C057924:batracylin; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000123:Acetyltransferases; D014453:Glucuronosyltransferase