Conjugation of xenobiotics

Weitering JG, Kriggsheld KR, Mulder GJ. 1979. The availability of inorganic sulfate as a rate limiting factor in the sulfate conjugation of xenobiotics in the rat. Biochem Pharmacol 28 757-762. 

Role of Gut Microflora in Metabolism of Glutathione Conjugates of Xenobiotics... 

The other primary Phase II metabolic pathway is glucuronidation, which involves the formation ofglucuronic acid conjugates of xenobiotics. This is catalyzed by a family of UDP-glucuronosyl transferases (UGTs) in the presence of uridine diphosphate... 

Although bile acid conjugates with amino acids are normally excreted into bile, amino acid conjugates of xenobiotics are usually excreted into urine. Conjugation with endogenous amino acids facilitates urinary excretion because of the organic anion transport systems located in the kidney tubules. 

Although mercapturic acids, the N-acetylcysteine conjugates of xenobiotics, have been known since the early part of the twentieth century, only since the early 1960s has the source of the cysteine moiety (glutathione) and the enzymes required for the formation of these acids been identified and characterized. The overall pathway is shown in Figure 7.19. 

Rich in both phase I (principally the cytochromes P450, catalyzing hydrolysis, reduction, and oxidation reactions) and phase II (catalyzing conjugation of xenobiotic molecules with hydrophilic moieties) biotransforming enzymes, the liver is the metabolic center of the body. In fact, most of the field of biochemistry is concerned with its metabolic reactions. The liver essentially converts ingested food into a balanced cell culture medium via metabolic interconversion of amino acids, carbohydrates, and lipids and synthesizes many substances that are subsequently exported for use in other areas of... 

In several fish species and one marine crustacean, taurine conjugates of xenobiotic carboxylic acids have been Isolated from urine (fish) or hepatopancreas (Crustacea) and subjected to unequivocal chemical characterization (77-82). Table VIZ shows which acids are conjugated with taurine in some marine species. 

Figure 5. Conjugation of xenobiotic phenols with phosphate.

Malonate hemi-ester glucose conjugates of xenobiotics are one of the most common forms of complex glucoside conjugate produced In plants. They are formed by the action of malonyl CoA transferase on glucose conjugates In the presence of malonyl CoA as Indicated In Equation 14. At least 9 pesticides have been Isolated from 7... 

The conjugation of xenobiotics with glutathione (GSH) in higher plants was first demtxistrated to be a major enzymatic detoxication mechanism with the atrazine herbicide in sorghum, corn, and other atrazine resistant species (77-80) (Equation 15). Since this... 

The mechanism by which xenobiotic alcohols or esters are converted to fatty acid esters has not been studied. They could be formed by the action of lyase enzymes in the presence of fatty acid glyceryl esters, as in the conversion of farnesol to farnesol fatty acid esters (150). Some lipolytic acyl hydrolase enzymes from plants readily catalyze the transfer of lipid-bound fatty acids to low MW alcohol acceptors (150.151) and enzymes of this class could be responsible for the occasional formation of fatty acid conjugates of xenobiotic alcohols. Mechanisms involving fatty acid acyl CoA, phospholipids, or direct esterification with fatty acids might also be involved (1 ). 

Even though the number of glycoside conjugates of xenobiotics that have been synthesized so far Is limited, the methods described here are convenient both for large and small scale operations. No specific restrictions In synthesis of Isotopically labeled conjugates should be encountered due to the synthetic methods. 

Conjugation of 0-, N- and S-contalnlng functional groups with sulfate Is very common In animal systems. Sulfate Is transferred from adenosine 3 -phosphate-5 -sulfatophosphate (PAPS) by a variety of transfer enzymes. The mechanisms for sulfation of xenobiotics (74,75) and the chemistry of sulfate esters and related compounds and the synthesis of these have been reviewed (75-77). Syntheses of 0-, N- and S-sulfate conjugates of xenobiotics may be carried out by the methods described below. 

The formation of an amide bond by organic chemical methods Is usually accomplished by reacting the acid halogenlde and the amino acid unless the acid substrate contains other reactive groups. The acid chloride Is prepared directly with thlonyl chloride (244) or Indirectly via the formation of a mixed anhydride by use of another acid halogenlde (245,246). Isotoplcally labeled [(2,4-Dlchlorophenoxy)acetyl]valine was synthesized by a DCC catalyzed reaction between the acid and valine (247). A few examples of synthetic amino acid conjugates of xenobiotics are shown In Table X. Several taurine conjugates of both alkanolc and benzylic acids have been synthesized and their physical properties determined by Idle et al. (2 ). 

Conjugates of xenobiotics eliminated in the urine and feces of exposed animals normally provide the basis upon which secondary metabolic pathways are proposed. In many cases, the mechanism of formation of the conjugate is readily apparent. Such is the case with phenols which are excreted as sulfate and glucuronide conjugates. The biochemical donors are known, the enzymes are well characterized and the substrate specificities of these enzymes are generally well established. Although this does not rule out the... 

The intracellular conjugation of xenobiotics with glutathione (GSH) results in their detoxication and adjusts their polarity to facilitate excretion from the cell (for recent reviews of GSH conjugation, see 1 and 2). Here the disposition of these GSH conjugates will be discussed. 

Many tissues are capable, at least vitro, of conjugation of xenobiotics with GSH (l)j the liver is assumed to be the most active, especially with Ingested xenobiotics, however GSH transferase activity has been detected in the Intestinal mucosa (6). The interorgan translocation of GSH conjugates formed in the intestinal... 

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