Mutagenic activity and DNA adduct formation by 1,2-epoxy-3-(p-nitrophenoxy)propane, an HIV-1 protease inhibitor and GST substrate

Acid protease inhibitor 1,2-epoxy-3-(p-nitrophenoxy)-propane (ENPP) is comm only used in research as a substrate for glutathione-S-transferase activity (GST) and recently was found to inhibit human immunodeficiency virus 1 (HI V-1) protease. The question of DNA-adduct formation and mutagenicity was in vestigated and found that ENPP causes DNA damage and acts directly to induc e mutagenicity in Salmonella. Using HPLC analysis, ENPP was shown to bind c ovalently to guanine residues. The Salmonella mutagenicity assay indicated that ENPP enhanced the mutation frequencies in the base-substitution strain TA00 by more than 20 times above the background. Its mutagenic potency was comparable to that of well-known carcinogens, N-methyl-N-nitrosourea (MNU) and aflatoxin B-1-8,9-epodde (AFB(1)-8,9-epoxide). The results suggest tha t ENPP should be classified as a mutagenic compound and a potential carcino gen. (C) 1999 Academic Press.