Most solvents and drugs are lipophilic, which facilitates their transport in the blood by lipoproteins and penetration through lipid components of cell membranes.
The reactions that metabolize xenobiotics into nontoxic products, or activate xenobiotics to generate toxic compounds (
Fig. 8.3
Fig. 8.2), occur in two phases. In phase I reactions, chemicals can undergo hydrolysis, oxidation, or reduction. Products of phase I reactions often are metabolized into water-soluble compounds through phase II reactions of glucuronidation, sulfation, methylation, and conjugation with glutathione (GSH). Water-soluble compounds are readily excreted.
Toxicity Distribution to tissues Storage
Fig. 8.2 Human exposure to pollutants. Pollutants contained in air, water, and soil are absorbed through the lungs, gastrointestinal (GI) tract, and skin. In the body, they may act at the site of absorption, but they generally are transported through the bloodstream to various organs, where they are stored or metabolized. Metabolism of xenobiotics may result in the formation of water-soluble compounds, which are excreted, or in activation of the agent, creating a toxic metabolite.
• The most important cellular enzyme system involved in phase I reactions is the cytochrome P-450 system. The P-450 system is present in organs throughout the body, but it is most active in the endoplasmic reticulum (ER) of the liver. The system catalyzes reactions that may either detoxify xenobiotics or convert xenobiotics into active compounds that cause cellular injury. Both types of reactions may produce, as a byproduct, reactive oxygen species (ROS), which can cause cellular damage (discussed in Chapter 2). Examples of metabolic activation of chemicals through the P-450 system are the conversion of carbon tetrachloride to the toxic trichloromethyl free radical, and the generation of a DNA-binding
Xenobiotic Elimination Nontoxic metabolite Reactive metabolite Effects on cellular molecules (enzymes, receptors, membranes, DNA)
Fig. 8.3 Xenobioticmetabolism.Xenobioticscanbemetabolizedtonontoxicmetabolitesandeliminatedfromthebody(detoxification).However,theirmetabolismalsomayresultinformationofareactivemetabolitethatistoxictocellularcomponents.Ifrepairisnoteffective,short-andlong-termeffectsdevelop.(Modified from Hodgson E: Atextbookofmoderntoxicology,ed 3, Fig. 1–1. Hoboken, NJ, 2004, John Wiley & Sons.) metabolite from benzo[a]pyrene, a carcinogen present in cigarette smoke. The cytochrome P-450 system also participates in the metabolism of a large number of common therapeutic drugs such as acetaminophen, barbiturates, and anti-convulsants, and in alcohol metabolism (discussed later).
• P-450 enzymes vary widely in activity among different people, owing to both polymorphisms in the genes encoding the enzymes and interactions with drugs that are metabolized through the system. The activity of the enzymes also may be decreased by fasting or starvation, and increased by alcohol consumption and smoking.