Introduction to ENVIRONMENTAL TOXICOLOGY Impacts of Chemicals Upon Ecological Systems - CHAPTER 9

CHAPTER 9 Biotransformation, Detoxification, and Biodegradation INTRODUCTION As mentioned in Chapter 5, following the entry into a living organism and translocation, a foreign chemical may be stored, metabolized, or excreted (Figure 5.2). When the rate of entry is greater than the rate of metabolism and/or excretion, storage of the chemical often occurs. Storage or binding sites may not be the sites of toxic action, however. For example, lead is stored primarily in the bone, but acts mainly on the soft tissues of the body. If the storage site is not the site of toxic action, selective sequestration may be a protective mechanism, since only the freely circu-lating form of the foreign chemical produces harmful effects. Some chemicals that are stored may remain in the body for a long time without exhibiting direct harmful effects. DDT may be considered as an example. Accumu-lation or buildup of free chemicals may be prevented, until the storage sites are saturated. Selective storage limits the amount of foreign chemicals to be excreted, however. Since bound or stored toxicants are in equilibrium with their free forms, a chemical will be released from the storage site as it is metabolized or excreted. On the other hand, accumulation may result in illnesses that develop slowly, as exemplified by fluorosis and lead and cadmium poisoning. METABOLISM OF ENVIRONMENTAL CHEMICALS: BIOTRANSFORMATION Subsequent to the entry of an environmental chemical into an organism such as a mammal, chemical reactions occur within the body to alter the structure of the chemical. This metabolic conversion process is known as biotransformation and occurs in any of several tissues and organs such as the intenstine, lung, kidney, skin, and liver. Figure 9.1 The two phases of xenobiotic metabolism. By far the largest number of these chemical reactions are carried out in the liver. The liver metabolizes not only drugs but also most of the other foreign chemicals to which the body is exposed. Biotransformation in the liver is thus a critical factor not only in drug therapy but also in the body’s defense against the toxic effects of a wide variety of environmental chemicals (Kappas and Alvares 1975). The liver plays a major role in biotransformation because it contains a number of nonspecific enzymes responsible for catalyzing the reactions involved. As a result of the process xenobiotics are converted to more water-soluble and more readily excretable forms. While the purpose of such metabolic processes is probably to reduce the toxicity of chemicals, this does not prove to be always the case. Occasionally the metabolic process converts a xenobiotic to a reactive electrophile that is capable of causing injuries through interaction with liver cell constituents (Reynolds 1977). Types of Biotransformation The process of xenobiotic metabolism includes two phases commonly known as Phases I and II. The major reactions included in Phase I are oxidation, reduction, and hydrolysis, as shown in Figure 9.1.Among the representative oxidation reactions are hydroxylation, dealkylation, deamination, and sulfoxide formation, whereas reduction reactions include azo reduction and addition of hydrogen. Such reactions as splitting of ester and amide bonds are common in hydrolysis. During Phase I, a chemical may acquire a reactive group such as OH, NH2, COOH or SH. Phase II reactions, on the other hand, are synthetic or conjugation reactions. An environmental chemical may combine directly with an endogenous substance, or may be altered by Phase I and then undergo conjugation. The endogenous substances commonly involved in conjugation reactions include glycine, cysteine, glutathione (GSH), glucuronic acid, sulfates, or other water-soluble compounds. Many foreign compounds sequentially undergo Phase I and Phase II reactions, whereas others undergo only one of them. Several representative reactions are shown in Figure 9.2. Mechanisms of Biotransformation In the two phases of reactions shown in Figure 9.1, the lipophilic foreign com-pound is first oxidized so that a functional group (usually a hydroxyl group) is introduced into the molecule. This functional group is then coupled by conjugating enzymes to a polar molecule so that the excretion of the foreign chemical is greatly facilitated. Figure 9.2 Detoxification pathways. The NADPH-cytochrome P-450 system, commonly known as the mixed-function oxygenase (MFO) system, is the most imporant enzyme system involved in the Phase I oxidation reactions. Cytochrome P-450 system, localized in the smooth endoplasmic reticulum of cells of most mammalian tissues, is particularly abundant Figure 9.2 (continued) in the liver. This system contains a number of isozymes which are versatile in that they catalyze many types of reactions including aliphatic and aromatic hydroxylations and epoxidations, N-oxidations, sulfoxidations, dealkylations, deaminations, dehaloge-nations and others (Wislocki et al. 1980). These isozymes are responsible for the oxi-dation of different substrates or for different types of oxidation of the same substrate. Carbon monoxide binds with the reduced form of the cytochrome, forming a complex with an absorption spectrum peak at 450 nm. This is the origin of the name of the enzyme. As a result of the complex, inhibition of the oxidation process occurs. At the active sites of cytochrome P-450 is an iron atom that, in the oxidized form, binds the substrate (SH) (Figure 9.3). Reduction of this enzyme-substrate complex then occurs, with an electron being transferred from NADPH via NADPH cytochrome P-450 Figure 9.2 (continued) reductase. This reduced (Fe2+) enzyme-substrate complex then binds molecular oxygen in some unknown fashion, and is then reduced further by a second electron, possibly donated by NADH via cytochrome b5 and NADH cytochrome b5 reductase. The enzyme-substrate-oxygen complex splits into water, oxidized substrate, and the oxidized form of the enzyme. The overall reaction is therefore: SH + O2 + NADPH + H+ ® SOH + H2O + NADP+ (9.1) where SH is the substrate. As shown in the above equation, one atom from molecular oxygen is reduced to water and the other is incorporated into the substrate. The requirements for this enzyme system are oxygen, NADPH, and Mg2+ ions. Contrary to the cytochrome P-450 system, most hepatic Phase II enzymes are located in the cytoplasmic matrix. In order for these reactions to occur efficiently, adequate activity of the enzymes involved is essential. In addition, it is clear that ... - tailieumienphi.vn