BIOACTIVATION AND INACTIVATION OF AFLATOXIN B-1 BY HUMAN, MOUSE AND RAT-LIVER PREPARATIONS - EFFECT ON SCE IN HUMAN MONONUCLEAR LEUKOCYTES

The purpose of this study was to investigate the use of human and anim al subcellular liver fractions in an in vitro evaluation of carcinogen ic risk. The bioactivation and bioinactivation of the known genotoxic carcinogen aflatoxin B-1 by human, mouse and rat liver preparations wa s investigated using the SCE assay in human lymphocytes as a genotoxic endpoint. There was a 10-fold variation in SCE response (1.1-11.6 SCE /Cell) in human mononuclear leucocytes (MNLs) after aflatoxin B-1 was activated by human liver microsomes (n=6). Activation correlated with the CYP1A2 phenotype of livers (r=0.8; p<0.05), but there was no corre lation with either GST M1 genotype or epoxide hydrolase phenotype. Mou se liver microsomes activated aflatoxin B-1 to a greater extent [(1 mu M) 12.8+/-2.51 SCE/Cell] than either rat [(10 mu M) 12.0+/-3.84 SCE/C ell] or human (L25) [(10 mu M) 8.8+/-2.00 SCE/Cell] liver microsomes. The addition of mouse liver cytosol and reduced glutathione (GSH) sign ificantly (p<0.001) reduced aflatoxin B-1-dependent genotoxicity, wher eas the addition of either human or rat cytosol (+GSH) was without eff ect. These data indicate that species variation in both bioactivation and bioinactivation can exist. Therefore there is a necessity for care ful selection of activation systems from species whose biochemical pro file reflects that of man.