Biotransformation water-soluble substances

A factor common to each of these processes is that substances must past through one or more cellular membranes. Small, lipophilic molecules are the substances that pass most easily through such membranes. The key connection here is that the chemical properties that are desirable in solvents require them to be composed of small, lipophilic molecules. Thus, solvents are some of the most easily absorbed and distributed in the body. However, the most easily excreted substances are those that are water soluble. Thus, the solvents relative inertness results in storage in the body rather than in biotransformation, which in turn prevents elimination from the body. Prolonged exposure to solvents, therefore, can result in the accumulation of a toxic concentration of that substance. This example is one of many in science in which properties that are desirable for one purpose can be detrimental for others. 

The term biotransformation is defined as biochemical changes in a substance through autometabolic processes. In this way, lipophilic substances can be converted into water-soluble (= excretable) metabolites in the liver. 

The enzyme systems involved in biotransformation are largely substrate-nonspecific. Therefore, they are not only able to convert exogenous or endogenous lipophilic substances into water-soluble metabolites, but also to intervene in the metabolism of endogenous substances (e. g. bile adds, hormones). These enzymes are mainly localized structure-bound in the biomembranes or found non-structure-bound as soluble enzymes. About 5% of the total protein reserves of the liver are needed for the bio transformation of enzymes. 

As mentioned previously, the biotransformation of lipophilic xenobiotics by Phase I and Phase II reactions might be expected to produce a stable, water-soluble, and readily excretable compound. However, there are examples of hepatic biotransformation mechanisms by which xenobiotics are converted to reactive electrophilic species. Unless detoxified, these reactive electrophiles may interact with a nucleophilic site in a vital cell constituent, leading to cellular damage. There is evidence that many of these reactive substances bind covalently to various macromolecular constituents of liver cells. For example, carbon tetrachloride, known to be hepatotoxic, covalently binds to lipid components of the liver endoplasmic reticulum (Reynolds and Moslen 1980). Some of the reactive electrophiles are carcinogenic as well. 

Cytochrome P450 electron transport systems are an important feature of biotransformation in animal bodies. Biotransformation is a series of enzyme-catalyzed processes in which potentially toxic and usually hydrophobic substances are converted into less toxic water-soluble derivatives that can then be more easily excreted. Substrates for biotransformation include endogenous substances, such as cholesterol, and foreign molecules, called xenobiotics, such as drugs and nonnutritive components of food (e.g., glycosides and numerous fatty acid and amino acid derivatives). 

Metabolism, or biotransformation, is the process of ehemical transformation of a toxicant to different structures, called metabolites, which may possess a different toxicity profile than the parent compound. Biotransformation affects both endogenous chemicals exogenous (xenobiotic) entities. Metabolism can result in a transformation product that is less toxie, more toxic or equitoxic but in general more water soluble and more easily excreted. Chemical modification can alter biological effects through toxication of a substance, also called bioactivation, which refers to the situation where the metabolic process results in a metabolite that is more toxic than the parent. If the metabolite demonstrates lower toxicity than the parent compound, the metabolic process is termed detoxication. These processes can involve both enzymatic and non-enzymatic processes, all of which should be familiar to undergraduate and graduate chemists. 

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). 

---