Phase II or Conjugation Reactions

Phase I or functionalization reactions do not always produce hydrophilic or pharmacologically inactive metabolites. Various phase II or conjugation reactions, however, can convert lliese metabolites to mote poltu and water-soluble products. Many conjugativc enzymes accomplish this objective by at-... 

Compounds having polar constituents such as — OH, — NH2 or —COOH, or acquiring them by a phase I reaction, may undergo a phase II or conjugation reaction. The major conjugation reactions are listed in Table 30.5. 

A number of enzyme systems have evolved in animals and plants which effectively convert lipophilic xenobiotics to more polar compounds that are efficiently excreted. Phase I enzymes, responsible for oxidation, reduction, and/or hydrolysis, are integrated with phase II or conjugation enzymes for reactions of both types and are normally required for the formation of products polar enough to be readily excreted. The intracellular level of these enzymes, and thus, the capacity for biotransformation, increases in a coordinate fashion in response to exposure to xenobiotic compounds. This response is... 

Plant biotransformation parallels liver biotransformation and is conceptually divided into three phases. Phase I typically consist of oxidative transformations in which polar functional groups such as OH, NH2, or SH are introduced. However, reductive reactions have been observed for certain nitroaromatic compounds. Phase II involves conjugation reactions that result in the formation of water soluble compounds such as glucosides, glutathiones, amino acids, and malonyl conjugates or water-insoluble compounds that are later incorporated or bound into cell wall biopolymers. In animals, these water-soluble Phase H metabolites would typically be excreted. In Phase III, these substances are compartmentalized in the plant vacuoles or cell walls. For additional details, the reader is referred to reviews on the subject by Komossa and Sandermann (1995), Pflugmacher and Sandermann (1998), and Burken (2003). Enzymatic conversion rates typically follow Michaelis-Menten kinetics and are temperature-dependent (Larsen et al., 2005 Yu et al., 2004,2005, 2007). 

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reactions, classically referred to as phases one and two. Phase I is a functionalization of the lipophilic compound that can be used to attach a conjugate in Phase II. The conjugated product is usually sufficiently water-soluble to be excretable into the urine. The most important biotransformations of Phase I are aromatic and aliphatic hydroxylations catalyzed by cytochromes P450. Other Phase I enzymes are for example epoxide hydrolases or carboxylesterases. Typical Phase II enzymes are UDP-glucuronosyltrans-ferases, sulfotransferases, N-acetyltransferases and methyltransferases e.g. thiopurin S-methyltransferase. 

Phase II This phase consists of conjugation reactions. If the metabolite from Phase I metabolism is sufficiently polar, it can be excreted by the kidneys. However, many metabolites are too lipophilic to be retained in the kidney tubules. A subsequent conjugation reaction with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid or an amino acid results in polar, usually more water-soluble compounds that are most often therapeutically inactive. Glucuronidation is the most common and the most important conjugation reaction. Neonates are deficient in... 

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