Aflatoxin dihydrodiol

Trichloroethylene Vinyl chloride CYP3A4 Acetaminophen Aflatoxin Bi and Gi 6-Aminochrysene Benzo[a]pyrene 7,8-dihydrodiol Cyclophosphamide Ifosphamide 1-Nitropyrene Sterigmatocystin Senecionine... 

CYP3A4 acetaminophen aflatoxin Bj and Gj 6-aminochrysene henzo[n]pyrene 7,8-dihydrodiol cyclophosphamide Ifosphamide 1-Nitropyrene sterigmatocystin senecionine... 

Fig. 10.30. Structure of aflatoxin B1 exo-8,9-epoxide (10.132), the dihydrodiol resulting from hydrolysis (10.133), and the reactive a-hydroxy dialdehyde (10.134) that exists in equilibrium with the diol under alkaline conditions [204]...

In the pH range of 5 - 10, H20-catalyzed hydrolysis is the predominant mechanism (see Fig. 10.11, Pathway b), resulting in the formation of the (8R,9R)-dihydrodiol (10.133, Fig. 10.30). Thus, aflatoxin B1 exo-8,9-epoxide is possibly the most reactive oxirane of biological relevance. Such an extreme reactivity is mostly due to the electronic influence of 0(7), as also influenced by stereolectronic factors, i.e., the difference between the exo- and endo-epoxides. The structural and mechanistic analogies with the dihydro-diol epoxides of polycyclic aromatic hydrocarbons (Sect. 10.4.4) are worth noting. 

A further remarkable finding in the hydrolysis of aflatoxin B1 exo-8,9-epoxide is the relative instability of the dihydrodiol, which under basic conditions exists in equilibrium with an aflatoxin dialdehyde, more precisely a furofuran-ring-opened oxy anionic a-hydroxy dialdehyde (10.134, Fig. 10.30). The dihydrodiol is the predominant or exclusive species at pH < 7, whereas this is true for the dialdehyde at pH >9, the pK value of the equilibrium being 8.2 [204], The dialdehyde is known to form Schiff bases with primary amino groups leading to protein adducts. However, the slow rate of dialdehyde formation at physiological pH and its reduction by rat and human aldo-keto reductases cast doubts on the toxicological relevance of this pathway [206]. 

Table 8.2 Formation of Aflatoxin B Dihydrodiol by Liver Microsomes...

Ramsdell, H. S., and Eaton, D. L., Mouse liver glutathione S-transferase isoenzyme activity toward aflatoxin B,-8,9-epoxide and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide. Toxicol. Appl. Pharmacol. 105, 216-225 (1990). 

---