Glucuronidation, acetylaminofluorene

The glucuronidation of bifirubin is discussed in Chapter 32 the reactions whereby xenobiotics are glu-curonidated are essentially similar. UDP-glucuronic acid is the glucuronyl donor, and a variety of glu-curonosyltransferases, present in both the endoplasmic reticulum and cytosol, are the catalysts. Molecules such as 2-acetylaminofluorene (a carcinogen), aniline, benzoic acid, meprobamate (a tranquilizer), phenol, and... 

Glucuronidation of the resulting hydroxyl derivatives is also induced by phenobarbital pretreatment. Consequently, pretreatment of animals with both these agents reduces the carcinogenicity of acetylaminofluorene. This illustrates the difficulty of predicting the effect of environmental influences on toxicity when multiple metabolic pathways are involved. 

Meerman JHN, Nijland C, Mulder GJ. 1987. Sex differences in sulfation and glucuronidation of phenol, 4-nitrophenol and N-hydroxy-2-acetylaminofluorene in the rat in vivo. Biochem Pharmacol 36 2605-2608. 

Acetylaminofluorene is not carcinogenic 2-acetylaminofluorene is carcinogenic. 2-Acetylami-nofluorene can be metabolized to form N-hydroxy-acetylaminofluorene and 2-aminofluorene, which may covalently bind to the DNA and macromolecules. Ring hydroxylation, however, leads to the formation and excretion of water-soluble conjugates (e.g., glucuronides) of the respective hydroxylated metabolites and detoxification. 

Jin CJ, Miners JO. Burchell B. et al. 1993. The glucuronidation of hydroxylated metabolites of benzo(a)pyrene and 2-acetylaminofluorene by cDNA-expressed human UDP-glucuronosyltransferases. Arch Environ Toxicol 27(3) 47-52. 

On the other hand, a few drugs and a number of xenobiotic aromatic amines are known to be A -hydroxyl-ated and then 0-glucuronidated. The reactivity of N-0-glucuronides, such as //-hydroxy-2-acetylaminofluorene glucuronide (Fig. 31.37) leads to heterolytic decomposition into a //-acetyl-A -arylnitrenium ion which then reacts with nucleic acids and proteins. ... 

---