Drug Metabolism

Substances foreign to the body, or xenobiotics, are metabolized by the same enzymatic pathways and transport systems that are utilized for dietary constituents. Xenobiotics to which humans are exposed include environmental pollutants, food additives, cosmetic products, agrochemicals, processed foods, and drugs. Many xenobiotics are lipophilic chemicals that, in the absence of metabolism, would not be efficiently eliminated and would accumulate in the body, possibly causing toxicity. Most xenobiotics are subjected to metabolic pathways that convert these hydrophobic chemicals into more hydrophilic derivatives that are readily eliminated in urine or bile.

The processes of drug metabolism that lead to elimination also play a major role in diminishing the biological activity of drugs. For example, phenytoin, an anticonvulsant used in the treatment of epilepsy, is virtually insoluble in water. Metabolism by phase 1 cytochrome P450 enzymes (CYPs) makes 4-OH-phenytoin, which is a substrate for phase 2 uridine diphosphate-glucuronosyltrans-ferases (UGTs) that produce a water soluble 4-glucuronate adduct that is readily eliminated. Metabolism also terminates the biological activity of the drug.

Paradoxically, these same enzymes can also convert certain chemicals to highly reactive toxic and carcinogenic metabolites. Depending on the structure of the chemical substrate, xenobiotic-metabolizing enzymes produce electrophilic metabolites that can react with nucleophilic cellular macromolecules such as DNA, RNA, and protein. Reaction of these electrophiles with DNA can sometimes result in cancer through the mutation of genes such as oncogenes or tumor suppressor genes. This potential for carcinogenic activity makes testing the safety of drug candidates of vital importance, particularly for drugs that will be used chronically.

THE PHASES OF DRUG METABOLISM Xenobiotic metabolism consists of phase 1 reactions (oxidation, reduction, or hydrolytic reactions) and phase 2 reactions, in which enzymes form a conjugate of the phase 1 product (Table 3-1). Phase 1 enzymes introduce functional groups (e.g., -OH, -COOH, -SH, -O-, or NH2) into the compound; these moieties do little to increase the water solubility of the drug but usually lead to drug inactivation. Metabolism, usually the hydrolysis of an ester or amide linkage, sometimes results in bioactivation of a drug. Inactive drugs that undergo metabolism to an active drug are called prodrugs. The antitumor drug cyclophosphamide is bioactivated to a cell-killing electrophilic derivative (see Chapter 51). Phase 2 enzymes facilitate the elimination of drugs and the inactivation of electrophilic and potentially toxic metabolites produced by oxidation. While many phase 1 reactions result in drug inactivation, phase 2 reactions produce a metabolite with improved water solubility and increased molecular weight, thereby facilitating drug elimination.

Phase 1 oxidation reactions are catalyzed by the superfamilies of CYPs, flavin-containing monooxygenases (FMOs), and epoxide hydrolases (EHs). The CYPs and FMOs comprise super-families containing multiple genes. The phase 2 enzymes include several superfamilies of conjugating enzymes, such as the glutathione-S-transferases (GSTs), UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), N-acetyltransferases (NATs), and methyltransferases (MTs). These conjugation reactions usually require the substrate to have oxygen (hydroxyl or epoxide groups), nitrogen, or sulfur atoms that serve as acceptor sites for a hydrophilic moiety (e.g., glu-tathione, glucuronic acid, sulfate, or an acetyl group) that is covalently conjugated to an acceptor site on the molecule, as in the example of phenytoin. In general, oxidation by phase 1 enzymes either adds or exposes a functional group, permitting the products to then serve as substrates for phase 2 conjugating or synthetic enzymes.

SITES OF DRUG METABOLISM Xenobiotic-metabolizing enzymes are expressed in most tissues in the body; the highest levels are found in the gastrointestinal (GI) tract (e.g., liver, small intestine, and colon). The high concentration of xenobiotic-metabolizing enzymes in GI epithelium mediates the initial metabolic processing of most oral drugs and is the initial site for first-pass metabolism of drugs. Absorbed drug then enters the portal circulation and transits to the liver, which is the major "metabolic clearing house" for both endogenous chemicals (e.g., cholesterol, steroid hormones, fatty acids, and proteins) and xenobiotics. While some active drug may escape first-pass metabolism in the GI tract and liver, subsequent passes through the liver result in further metabolism of the parent drug until it is eliminated. Other organs that contain significant xenobiotic-metabolizing enzymes include the nasal mucosa and lung, which play important roles in the firstpass metabolism of airborne pollutants and of drugs that are administered as aerosols.

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