Glucuronic acid, glucuronidation

Study of the metabolism of dinoseb and its acetate and of binapacryl in rabbits showed that 2-amino-6-sec-butyI-4-nitrophenol (39) is formed aiid excreted as O-conjugate with glucuronic acid, glucuronide (40). In rats this metabolism appears only in traces, but for both compounds the oxidation of the side chain — and thus the formation of -methyl-/ -(2-hydroxy-3,5-dinitrophenyl)propionic acid (41) in considerable quantities, also excreted in the urine — has b n detected. The evacuation of nitro compounds from warm-blooded organisms is relatively slow. 

D-Glucuronic acid is widely distributed in both the plant and animal worlds. In humans, it is an important component of the acidic polysaccharides of connective tissues. The body also uses it to detoxify foreign phenols and alcohols. In the liver, these compounds are converted to glycosides of glucuronic acid (glucuronides), to be excreted in the urine. The intravenous anesthetic propofol (Problem 10.43), for example, is converted to the following water-soluble glucuronide and then excreted in the urine ... 

Glucuronidation. Complexation of the steroid to glucuronic acid, most predominantiy via the C-3 hydroxyl, leads to a considerable portion of the excreted metabohtes of ah. glucocorticoids. In infants, sulfurylation (formation of a sulfate ester) is also predominant (16). 

The uronic acid pathway is the source of glucuronic acid for conjugation of many endogenous and exogenous substances before excretion as glucuronides in urine and bile. 

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... 

Hepatic metabolism No Yes oxidation and hydroxylation induces liver enzymes to increase its metabolism and other drugs Yes oxidation and conjugation Yes oxidation and glucuronide conjugation Yes glucuronic acid conjugation Induces its own metabolism in normal volunteers... 

Formation of. glucuronide conjugates is a major metabolic conversion for many lipid-soluble compounds. The product glucuronides are more water soluble and usually more readily excreted. The glucuronic acid donor in this reaction is... 

UDPG was the first of a whole new class of nucleotides, in which the uridine diphosphate group is attached to a monosaccharide. Two important members of the class are uridine diphosphate glucuronic acid, the intermediate in the synthesis of glucuronides and of many other compounds, and uridine diphosphate N-acetylglucosamine which is an intermediate in the synthesis of mucopolysaccharides. Uridine diphosphate muramic acid was isolated by Park (P2) from Staphylococcus aureus... 

Many drugs and metabolites are metabolized by conjugation with sulfate or glucuronic acid as described in Chapter 7. Sulfate conjugates can be hydrolyzed back to the alcohol or phenol. Glucuronide conjugates can involve a wider variety of functional groups and... 

The predicted metabolites are also the starting point for the phase II metabolic prediction, to find where glucuronidation could occur. All the probable metabolites obtained from CYP metabolism reactions are submitted to a possible phase II reaction catalyzed by UGTs, using the UGT structure(s) as a template. The accessibility component is computed in the UGTcavity to prioritize glucuronic acid transfer. The final metabolite structures are then reported in graphical output or saved to a file. 

The fate of chlordecone in humans involves uptake by the liver, enzymatic reduction to chlordecone alcohol, conjugation with glucuronic acid, partial conversion to unidentified polar forms, and excretion of these metabolites mainly as glucuronide conjugates into bile (Fariss et al. 1980 ... 

---