Bioactivation and inactivation of aflatoxin B1 by human, mouse and rat liver preparations: effect on SCE in human mononuclear leucocytes.
The purpose of this study was to investigate the use of human and animal subcellular liver fractions in an in vitro evaluation of carcinogenic risk. The bioactivation and bioinactivation of the known genotoxic carcinogen aflatoxin B1 by human, mouse and rat liver preparations was 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 B1 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 correlation with either GST M1 genotype or epoxide hydrolase phenotype. Mouse liver microsomes activated aflatoxin B1 to a greater extent [(1 micro M) 12.8 +/- 2.51 SCE/Cell] than either rat [(10 micro M) 12.0 +/- 3.84 SCE/Cell or human (L25) [(10 micro M) 8.8 +/- 2.00 SCE/Cell liver microsomes. The addition of mouse liver cytosol and reduced glutathione (GSH) significantly (p < 0.001) reduced aflatoxin B1-dependent genotoxicity, whereas the addition of either human or rat cytosol (+GSH) was without effect. These data indicate that species variation in both bioactivation and bioinactivation can exist. Therefore there is a necessity for careful selection of activation systems from species whose biochemical profile reflects that of man.
Wilson
A S
AS
Department of Pharmacology and Therapeutics, University of Liverpool, UK.
Williams
D P
DP
Davis
C D
CD
Tingle
M D
MD
Park
B K
BK
D016604:Aflatoxin B1 / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D003593:Cytoplasm / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests / Q000379:methods*; D051381:Rats; D012854:Sister Chromatid Exchange; D013045:Species Specificity
D016604:Aflatoxin B1; D005978:Glutathione