Oxidation aflatoxin

Moving to toxic compounds, we encounter the infamous aflatoxin Bl, a mycotoxin considered to be a major cause of human liver cancer in some parts of the world. Thus, there are some estimates that, in China, as many as 1 in 10 adults die from liver cancer caused by aflatoxin [205]. Oxidation of... 

Electron-rich alkenes are the more reactive jr-bond snbstrates towards epoxidation by the electrophilic dioxiranes Some typical examples of these oxidations are snm-marized in Scheme 2. Since the resnlting epoxides are nsnally hydrolytically and ther-molytically qnite labile, snch oxidations are best carried ont with isolated dioxiranes. For example, the 8,9 epoxide of the well-known aflatoxin B, postnlated as potent carcinogen in the oxidative metabolism of this natural product, escaped numerous efforts to prepare it by conventional epoxidations because of its sensitivity towards hydrolysis . The synthesis of this labile epoxide was readily accomplished by employing a solution of the isolated DMD at room temperature (equation 2), and its mutagenicity unequivocally... 

The importance of chiral factors in disposition and toxicity has been fully recognized only relatively recently, although important examples have been known for some time. For instance the S(—) enantiomer of thalidomide is known to have greater embryotoxicity than the R(+) enantiomer (see chap. 7). Another example in which a particular isomer of a metabolite is responsible for a carcinogenic effect is the exo-oxide of aflatoxin Bi, discussed later in this chapter (Fig 5.14). 

Figure 5.14 Routes of oxidative metabolism of aflatoxin showing activation to an epoxide catalyzed by CYP1A2 and CYP3A4 and conjugation with glutathione catalyzed by a-GST. The 8,9-exoepoxide is the enantiomer, which binds extensively to DNA and is carcinogenic. The endoepoxide binds less readily. Abbreviation. a-GST, a-glutathione transferase.

AF-2, 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide AFBj, aflatoxin B1 4NQ0, 4-nitroquinoline 1-oxide B [sJP, benzota]-pyrene DEN, diethylnitrosamine DMN, dimethylnitrosamine. 

Adducts to hemoglobin are perhaps the most useful means of biological monitoring by adduct formation. Hemoglobin is, of course, present in blood, which is the most accurate type of sample for biological monitoring. Adducts to blood plasma albumin are also useful monitors and have been applied to the determination of exposure to toluene diisocyanate, benzo(a)pyrene, styrene, styrene oxide, and aflatoxin Bj. The DNA adduct of styrene oxide has been measured to indicate exposure to carcinogenic styrene oxide.12... 

The toxification of benzo[a]pyrene and most other polycyclic aromatic hydrocarbons to mutagenic intermediates by continuous cell lines has been reported dozens of times, whereas toxification of aflatoxin Bj to mutagenic intemediates in some cell lines does not occur.225 These data can be explained by the fact that the forms of P-450 necessary for polycyclic-hydrocarbon toxification remain in cultured primary and continuous cell lines, whereas the forms of P-450 responsible for the 2,3-oxide formation of aflatoxin Bj disappear rapidly in culture, for unknown reasons. Studies involving cultured human tissues may have this same major liability. The choice of cell culture for any particular compound therefore can be important. 

Epoxidation and hydroxylation A-Dealkylation O-Dealkylation -Dealkylation -Oxidation A-Oxidation P-Oxidation Desulfuration Dehalogenation Nitro reduction Azo reduction Cytochrome P450 (CYP) Aflatoxin, aldrin, benzo[a]pyrene, bromobenzene, naphthalene Ethylmorphine, atrazine, dimethylnitrocarbamate, dimethylaniline p-Nitroanisole, chlorfenvinphos, codeine Methylmercaptan Thiobenzamide, phorate, endosulfan, methiocarb, chlorpromazine 2-Acetylaminofluorene Diethylphenylphosphine Parathion, fonofos, carbon disulfide CCLt, CllCb Nitrobenzene O-Aminoazotoluene Flavin-Containing Monooxygenase (FMO)... 

Figure 24.12. Examples of DNA adducts and oxidized guanine nucleotide. (A) Benzo[a]pyrene-7,8-diol-9,10-epoxide-M-2 guanine adduct. (B) Aflatoxin epoxide N7 guanine adduct. (C) 8-Oxoguanine is commonly produced by reactive oxygen species, dR = deoxyribose.

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