Module 3: Toxicology - Section 2: General Principles of Toxicology

TOX2.5: Distribution

DISTRIBUTION:

Blood is the primary method of distribution with some of the toxic substances being removed by the lymph and lung macrophages. The physiological and physicochemical nature of a substance determines the manner of distribution. The lipid-solubility of substances allows them to penetrate certain barriers. Sometimes toxic agents may bind to cellular proteins and as a result accumulate in tissues. Alternatively a difference in pH gradient can lead to the accumulation of toxic substances in one area as opposed to another. Substances such as DDT or Dioxin can accumulate in body fat tissues and still be present in equilibrium between fat and bllod several years later.

Distribution is dependent upon blood flow to an organ and ease of passage across cell membranes.

Biotransformation and Metabolism:

The enzymes involved with biotransformation or metabolism occur in almost all tissues of the body, although certain tissues are much more active in metabolism than are others. In order of quantitative importance are the liver > kidney > GI tract, lung > other tissues. The enzymes responsible for biotransformation of xenobiotics, (foreign chemical substances), are also involved in the metabolism of natural substances. These enzymes are predomitely located in membranes (e.g., endoplasmic reticulum, or microsomes) and are also found in the cytoplasm of cells. The Phase 1 transformations, (e.g., oxidation, reduction, hydroxylation, nitrosation etc.) of lipid-soluble substances most often results from an action of a family of hemoprotein oxygenases called Mixed Function Oxygenases, MFO, or cytochrome P-450 enzymes, ( so called because they absorb light at a wavelength of approximately 450 nanometers. Typically Phase 1 transformations add, create or uncover chemically reactive functional groups and do not greatly affect hydrophillicity or water solubility. These heme containing proteins require NADPH and molecular oxygen and exhibit some, but not strict, substrate specificity. These enzymes can be induced to become more active through action of some other foreign compounds. Typical inducers of Phase 1 enzymes include ethyl alcohol, phenobarbitol, polyaromatic hydrocarbons, organochlorines such as DDT or Dioxins and a variety of pharmaceutic agents. In addition specific substrates typically induce the appropriate metablic enzymes, (ethyl alcohol induces alcohol and aldehyde dehydrogenases). Thus, the rate of metabolism can be increased due to occupational, behavioral or environmental factors.

Phase 2 biotransformations involve a group of transferases which conjugate aminoacids or other groups which typically decrease chemical reactivity and increase excretability. These enzymes add a polar water-soluble, endogenous substance (e.g., glucuronic acid, glutathione) to relatively lipid-soluble substances. The water-soluble metabolites, called conjugates, are usually readily excreted. The activity or amounts of transferases can also be increased by substrates or foreign compounds, and may be monitored in blood as what are termed liver enzymes or aminotransferases.

Some agents are metabolized at a high rate while others are metabolized slowly. The rate of metabolism is usually quite dependent on chemical structure and physical properties. In addition there is a great variability in the activity of certain metabolizing enzymes between individuals which appears to be under genetic control. For example there are fast versus slow acetylators, various isozymes of glucosyl-sulfo-transferases etc. which result in dramatic differences in metabolic rates of certain substances and thus risk of toxicity in certain individuals.

Phase 1 biotransformations of certain compounds can result in metabolites which are highly chemically reactive and capable of reacting with biologic tissues. Once formed, electrophillic metabolites such as epoxides, N-hydroxy compounds, etc., can react with nucleophilic groups on cellular macromolecules (proteins and nucleic acids) and alter cell function or result in mutation. Cell death can result, or genetic material may be altered. The formation of reactive metabolites is the basis for some severe toxicities and be the cause of chemically-induced carcinogenesis. Biotransformation, then, is a "double-edged sword". On one hand, it is often the major factor in determining the excretability of a substance. On the other hand, most xenobiotics must be activated to toxic metabolites. Lipid-soluble compounds would be retained for a long time in the body unless converted to more water-soluble metabolites which can be readily excreted. Metabolites may be pharmacologically or toxicologically active or they may be biologically inactive. A high degree of water solubility from Phase 2 conjugation processes usually imparts less activity because of limited distribution to tissues and rapid-excretion. Relatively lipid-soluble metabolites may be inactive because of an inability to fit receptors. For substances absorbed through the gastrointestinal tract there is a first pass effect wherein substances are biotransformed in the liver before they reach systemic circulation with overall lower systemic bioavailability.

Postgraduate Diploma in Occupational Health (DOH) - Modules 3: Occupational Medicine & Toxicology (Basic) by Profs Mohamed Jeebhay and Rodney Ehrlich, Health Sciences UCT is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 2.5 South Africa License. Major contributors: Mohamed Jeebhay, Rodney Ehrlich, Jonny Myers, Leslie London, Sophie Kisting, Rajen Naidoo, Saloshni Naidoo. Source available from here. For any updates to the material, or more permissions beyond the scope of this license, please email healthoer@uct.ac.za or visit www.healthedu.uct.ac.za. Last updated Jan 2007.
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