Hydroxylated metabolites, aflatoxin

Figure 5 represents the in vitro metabolism of AFBi by rats fed diets containing either 5T or 20% casein. The production of the hydroxylated metabolites AFQi and AFMj is depressed in animals fed the low protein diet, the depression of metabolism is similar to that seen with the N-demethylation of ethylmorphine. An exception to the depressed production of AFMi and AFQi is the enhanced production of an unidentified aflatoxin, tentatively termed AFXi- This metabolite is retained at the origin on TLC... 

Figure 5. The effect of dietary protein levels on the metabolism of aflatoxin to hydroxylated metabolites. Rats were fed semifurified diets consisting of either 5 casein or 20 casein as the protein source.

This metabolite was isolated by several groups78-80), and was assigned to be structure (15), the benzylic hydroxylated form of aflatoxin Gj(9). The structure was assigned on the basis of the similarity of spectra of the isolated compound with that of aflatoxin Gi(9), and the ready formation of a monoacetate under common acylation conditions. 

The desirability of having relatively copious quantities of the milk toxins for studies regarding their carcinogenicity, prompted Buchi and Weinreb139, 145 to develop a total synthesis of these metabolites. Notably, the only difference between aflatoxin Mi (13) and aflatoxin Bj (1) is the presence of the tertiary and benzylic hydroxyl functionality at C-14. Unfortunately, the methodologies utilized in the constructions of the toxins previously discussed are not applicable to this problem in that they inherently do not contain the necessary provisions for the initial presence, or the delayed introduction, of this C-14 hydroxyl. Therefore, a radically different approach was essential, which would provide for this contingency. 

Aflatoxin Bi (9.15, Scheme 9.1) is one of the most potent carcinogens known. There is a significant relationship between the presence of aflatoxins in the diet and the incidence of liver cancer. The reactive enol ether of aflatoxin Bi is epoxidized in the liver to form the active metabolite which may react with DNA. The adduct 2-(7V-7-guanyl)-3-hydroxyaflatoxin Bi (9.18) has been detected in the urine of test animals fed aflatoxin. Aflatoxin Bi is also hydroxylated by animals that have ingested it in their fodder. A carcinogenic metabolite, aflatoxin Mi (9.16), has been identified in the milk of these animals. 

Hydroxylation of aflatoxin B. Biichi et al effected hydroxylation of the carcinogen aflatoxin Bi (1) to the metabolite (2) and the epimeric alcohol by... 

While the aflatoxins B and G are major compounds of the fungus Aspergillus flavus, there are also minor aflatoxin constituents from this organism, e.g. hydroxylated derivatives of aflatoxin Bi (1) and B2 (2), the so-called milk-toxins . Ml (5) and M2 (6), which bear a hydroxy group at the junction of the two furan rings 19). They are called mOk toxins , because they are metabolites of aflatoxin Bi (1) and B2 (2), formed when cows get fed with contaminated foodstuffs. The toxins are then contained in the cow s milk. Other aflatoxins have a hydroxy group instead of... 

When feed contaminated with aflatoxins Bj and B2 is given to cows, aflatoxins Mj and M2 resulting from hydroxylation of the parent compounds may be found in milk in roughly 12 h. The transition factor, which is the ratio between the amount of ingested precursor (aflatoxin Bj) and excreted aflatoxin Mp is in the range of 100 1 to 300 1. The major part of this metabolite is excreted in the urine. Trace amounts of aflatoxin Mj also appear in milk after... 

Extensive methodology is available for the production of sterigmatocystin and the aflatoxins on stationary and submerged cultures on chemically defined media (Maggon et al., 1977). The amounts and relative proportions of aflatoxins B, B2, Gj, and G2 depend on the strain, balance of nutrients in the medium, and culture conditions. Lower pH and some trace metals, e.g., Mn Mg, and Va favored production of hydroxylated aflatoxins (Pai et al., 1975). In biosynthetic studies, it is essential to determine the rate of metabolite production, as the precursors must not only penetrate the synthetic site but must do so at a time when the enzyme systems mediating the synthetic reactions are present and active, i.e., the late stages in the... 

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