Conjugation, metabolic reaction

The concept of microbial models of mammalian metabolism was elaborated by Smith and Rosazza for just such a purpose (27-32). In principle, this concept recognizes the fact that microorganisms catalyze the same types of metabolic reactions as do mammals (32), and they accomplish these by using essentially the same type of enzymes (29). Useful biotransformation reactions common to microbial and mammalian systems include all of the known Phase I and Phase II metabolic reactions implied, including aromatic hydroxylation (accompanied by the NIH shift), N- and O-dealkylations, and glucuronide and sulfate conjugations of phenol to name but a few (27-34). All of these reactions have value in studies with the alkaloids. 

Phenol is a hydrolyzed metabolite of benzene and is itself further hydrolyzed or conjugated to produce other compounds. Therefore, the toxic effects of phenol exposure may be due to a combination of the parent compound and its metabolites. The major tissues in which metabolism appears to occur are the liver, gut, lung, and kidney (Cassidy and Houston 1984 Powell et al 1974 Quebbemann and Anders 1973 Tremaine et al. 1984). Since phenol, benzene, and their major metabolites all seem to compete for the same P450 and conjugating enzymes, metabolic reactions are presumed to be saturable. 

Whereas metabolic reactions of oxidation and reduction are universally recognized as being functionalization reactions, there has been some debate over whether reactions of hydrolysis should be classified as conjugations. This is a view we strongly oppose, as argued below. 

While some conjugation reactions fail to totally meet the above criteria, they all satisfy at least one criterion. But what about the reactions of hydrolysis On the one hand, these fulfil none of the three above criteria, with the partial exception that the molecule (water) that reacts with the substrate is a polar one. On the other hand, the metabolic reactions of hydrolysis modify pre-existing functional groups of the substrates and, thus, meet the definition of functionalization reactions. 

Conjugation-Deconjugation Reactions in Drug Metabolism and Toxicity , Ed. F. C. Kauffman, Springer Verlag, Berlin, 1994. 

Selective labelling of the two diastereotopic methyl groups of i-leucine (144) has enabled their fates during secondary metabolic reactions to be elucidated [66]. Moreover, in the context of protein interactions, differentiation of the leucine pro-R and pro-S methyl groups in protein NMR spectra allows molecular recognition phenomena to be studied [67]. Recently, efficient routes to both forms of Relabeled leucine, based on application of an auxiliary-controlled stereoselective conjugate addition reaction (Scheme 6.27) have been described [68]. Thus, starting... 

The second phase of metabolism consists of synthetic reactions that convert active compounds into inactive excretory products. Drugs that contain suitable chemical groups, such as —OH, —NHa, or —COOH, can undergo these synthetic conjugation reactions if not present in the parent compound, such drugs may be introduced during phase one reactions. Phase one and phase two metabolic reactions occur sequentially. 

The results of a comparative metabolism study of an aryl-sulfenyl derivative of carbofuran [2,2-dimethy1-2,3-dihydro-benzofuranyl-7 -methyl-N-(2-toluenesulfenyl)carbamate] in the house fly and white mouse Indicated the selective action of this compound to be a consequence of different metabolic pathways in insects and mammals (12). The arylsulfenyl group on the carbamate moiety allows the mammal to carry out metabolic reactions leading to less toxic products which are rapidly conjugated, while the toxic parent methylcarbamate is formed in the insect. 

Kauffman FC (1994) Conjugation-deconjugation reactions in drug metabolism and toxicity. 

Metabolism and elimination are critical in determining medication blood level and longevity of action. Two main categories of metabolic reactions are phase I reactions and phase 11 reactions. Phase 1 reactions are oxidative reactions that involve the cytochrome P450 system, and phase 11 reactions are conjugative reactions. The rate-limiting step for most compounds occurs through phase I metabolism. 

Conjugations. Conjugation reactions are Phase II metabolic reactions that are enzymatically catalyzed and involve the attachment of small polar molecules (glucuronic acid, sulphate, amino acids) to the drug. This, in turn, makes the drug more water soluble and... 

According to the second law, the dissipation function must be positive if not zero, which of course is to be expected here, since we are dealing with a spontaneously occurring passive process. The thermodynamic force A/x+, which contains both a concentration-dependent component and an electrical component, is the sole cause of the flow J+. In a system in which more than one process occurs, each process gives rise to a term in the dissipation function consisting of the product of an appropriate force and its conjugate flow. In the case of active transport of the cation, as found, for example, in certain epithelial tissues, the cation flux is coupled to a metabolic reaction. If we represent the flow or velocity of the reaction per unit area of membrane by Jr, the appropriate force driving the reaction is... 

After an oral dose of 6 mg/kg bw to rats, approximately 38% of the dose was exhaled as CO2, 50% was excreted as metabolites in the urine and 3% was present in faeces (Gingell et al., 1985). Concentrations were highest in liver, kidney and forestomach. The initial metabolic reactions are conjugation of the epoxide with glutathione, which is probably a chemical, not enzymatic, reaction, and hydration of the epoxide by epoxide hydrolase. The major metabolites in urine are jV-acetyl-5 -(3-chloro-2-hydroxypropyl)-L-cysteine (36% of the dose) and 3-chloro-1,2-propanediol (a-chlorohydrin) (4%). 

Most of the reactions that we will consider in this chapter involve addition of a proton to a carbon atom or removal of a proton attached to a carbon atom. A frequent metabolic reaction is addition of water to a carbon-carbon double bond that is conjugated with a carbonyl group. This transmits the polarization of the carbonyl group to a position located two carbon atoms further along the chain. 

Caffeic acid is metabolized by liver enzymes to give ferulic, vanillic acids and their glycine conjugates, which may be excreted into urine. In addition, dihydroferulic acid is produced by catechol o-methyltransferase in the liver. Because of the specificity of this enzyme, only ortho hydroxy-methoxy metabolites may be formed. These reactions may occur in rats as well in humans [15]. Fig. (2) shows the metabolic reactions of caffeic acid in body tissues. 

Nature has furnished the corrin ring of a conjugation system which enables the cobalt atom to carry on metabolic reactions tetradehydrocorrin, having a similar k system, is therefore a better model than octadehydrocorrin. 

---