Metabolism aflatoxin

Ellis EM, Judah DJ, Neal GE, Hayes JD. An ethoxyquin-indueible aldehyde reduetase from rat liver that metabolizes aflatoxin Bi defines a subfamily of aldoHceto reductases. Proc Natl Acad Sci USA 1993 90 10350-10354. 

The ability of liver preparations from various species to metabolize aflatoxin B, in vitro has been compared (Table XV). Since the species more sensitive (rabbit and trout) to the toxicity of aflatoxins formed relatively larger amounts of aflatoxicol metabolically, it had been suggested that the formation of this metabolite could serve as an indicator of toxicity for a given species (776, 367). In an attempt to determine if the levels of metabolic activity would correlate with differences in susceptibility between species, liver preparations from duck, rats, mice, monkeys, and humans were employed. No consistent relationship was detected between species sensitivity and either total metabolic activity or the preferential formation of specific metabolites. 

Aeruginoic acid — see ThiazoIe-4-carboxyIic acid, 2-o-hydroxyphenyI-Aetiocobalamin, 4, 420 Aflatoxin B biosynthesis, 3, 876 Aflatoxin B, metabolism, 1, 245 toxicity, 1, 136 Aflatoxin G, toxicity, 3, 676 ... 

E (1997) Mechanism of action of dietary chemoprotective agents in rat liver induction of phase I and II drug metabolizing enzymes and aflatoxin B1 metabolism . Carcinogenesis, 18 1729-38. 

Gradelet, S., Le Bon, A.M., Berges, R., Suschetet, M., and Astorg, P. 1998. Dietary carotenoids inhibit aflatoxin Bl-induced liver preneoplastic foci and DNA damage in the rat Role of the modulation of aflatoxin B1 metabolism. Carcinogenesis 19 403—411. 

Dietary Casein Levels and Aflatoxin Bi Metabolism in Rainbow Trout (Salmo gairdneri)... 

F. P. Guengerich, W. W. Johnson, Y. F. Ueng, H. Yamazaki, T. Shimada, Involvement of Cytochrome P450, Glutathione 5-Transferase, and Epoxide Hydrolase in the Metabolism of Aflatoxin B1 and Relevance to Risk of Human Liver Cancer , Environ. Health Perspect. 1996, 104 (Suppl. 3), 557 - 562. 

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... 

Previous studies have determined that aflatoxins are biosynthesized by the polyketide metabolic pathway and are considered secondary metabolites b ause... 

Inhibition of aflatoxin biosynthesis by neem extracts in fungal cells appear to occur in the very early stages of the biosynthetic pathway (i.e., prior to norsolorinic acid synthesis) because after the initiation of secondary metabolism, the inhibitory effect of the neem leaf constituents was lost (84). 

Halvorson MR, Phillips TD, Safe SH, et al. 1985. Metabolism of aflatoxin BI by rat hepatic microsomes induced by polyhalogenated biphenyl congeners. Appl Environ Microbiol 49(4) 882-886. 

Shepard EC, Phillips TD, Irvin TR. 1984. Aflatoxin BI metabolism in the rat Polyhalogenated biphenyl enhanced conversion to aflatoxin Ml. Xenobiotica 14(9) 741-750. 

In some cases, species differences in toxicity are due to more than one metabolic difference. For example, research on the fungal toxin aflatoxin B1 indicates that humans are particularly susceptible, more so than rodents, with rats being more susceptible than mice. Interestingly, cynomologous monkeys are also relatively insensitive probably due to the lack of constitutive CYP1A2. 

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.

Examples of initiators include alkylating agents, dime thy lsu If ate and ji-propiolactone, procarcinogens (requiring metabolic activation) such as benzo(a)pyrene, aflatoxin, and cyclophosphamide (Fig. 6.52) as follows ... 

Autrup, H., Schwartz, R.D., Essigmann, J.M., Smith, L., Trump, B.F. Harris, C.C. (1980b) Metabolism of aflatoxin Bj, benzo[a]pyrene, and 1,2-dimcthylhydrazine by cultured rat and human colon. Teratog. Carcinog. Mutag., 1, 3-13... 

Aflatoxin B, is regarded as hepatocarcinogen and genotoxic (2,9). Exhaustive reviews on toxicity, metabolism, and epidemiological studies are provided by IARC and more recently by several authors (2,4). 

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