ACTIVATION AND DETOXICATION OF AFLATOXIN B-1

Aflatoxin B-1 (AFB(1)) is a potent hepatocarcinogen in experimental an imals and a hazard to human health in several parts of the world. Impl ementation of rational intervention plans requires understanding of as pects of the roles of individual chemical steps involved in its dispos ition. AFB(1) is activated to AFB(1) exo-8,9-epoxide primarily by cyto chrome P450 (P450) enzymes, particularly P450 3A4. However, P450 3A4 a nd other P450s also oxidize AFB(1) to less dangerous products. The exo -epoxide is unstable in H2O (t(1/2) 1 s at 25 degrees C, k = 0.6 s(-1) ) and the diol product undergoes base-catalyzed rearrangement to a dia ldehyde that reacts with protein lysine residues. AFB(1) exo-8,9-epoxi de reacts with DNA to give adducts in high yield (> 98%). This interac tion is characterized by a K-d of similar to 1.4 mM, intercalation bet ween base pairs, and rapid reaction with the guanyl N-7 atom (k simila r to 40 s(-1)). A proton field on the periphery of DNA is postulated t o catalyze hydrolysis and also conjugation. Rat and especially human e poxide hydrolase show very little rate acceleration of hydrolysis of A FB, exo- or endo-8,9-epoxide. However, glutathione transferases (GSTs) can catalyze AFB(1) exo-8,9-epoxide conjugation. Kinetic analysis ind icates a range of ratios of k(cat)/K-d varying from 10 to 1700 s(-1) M -1, with the polymorphic GST M1-1 having the highest activity of the h uman GSTs, Studies with human hepatocytes indicate a major role for GS T M1-1 in AFB, conjugation and that the model chemoprotective agent ol tipraz can act by both inducing GSTs and inhibiting P450s. (C) 1998 El sevier Science B.V. All rights reserved.