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Fundamentals of Toxicologic Pathology
By Wanda M. Haschek Colin G. Rousseaux Matthew A. Wallig
Academic Press
Copyright © 2010 Elsevier Inc.
All right reserved. ISBN: 978-0-08-091932-4
Chapter One
Principles of Toxicology OUTLINE
The Effect of the Body on the Chemical 1 Absorption 1 Passage across Membranes 1 Distribution 2 Volume of Distribution 2 Barriers to Distribution 2 Biotransformation 3 Phase I Metabolism 3 Phase II Metabolism 4 Enzyme Location in Toxicity 4 Excretion 5 Urinary Excretion 5 Biliary Excretion 5 Pulmonary Excretion 6 Interaction of Chemical and the Body 6 Enzyme Induction and Inhibition 6 Activation, Induction, or Synergism 6 Inhibition 6 Dose Dependency and Site of Action 7 Organ Specificity for Toxicity 7 Site-Specific Interactions and Toxicity 7 Receptors and Enzymes 7 Direct and Cascade Effects 7 Nonspecific Interations and Toxicity 7 Electrophiles and Covalent Binding 7 Further Reading 8
THE EFFECT OF THE BODY ON THE CHEMICAL
ABSORPTION
Passage across Membranes
Simple Diffusion
With the process of simple diffusion there is no substrate specificity and no receptor requirements. It involves the entire membrane and depends solely on the lipid–water partition. Polar, or water-soluble, compounds are in equilibrium between ionized and non-ionized forms. The ionized form has such a low lipid–water partition that it is essentially insoluble in lipid membranes, and only the non-ionized portion is available for diffusion across the membrane. Ionization is dependent upon the pKa of the compound and the acidity of the environment. Due to the volume disparity between aqueous and lipid areas of the cell, diffusion is rate-limited by lipid solubility, increasing with increasing lipid solubility. Once through the membrane the substance re-equilibrates between ionized and non-ionized forms, depending on the pH of the aqueous intracellular environment.
Passage through Pores
Plasma membranes contain pores that allow small, ionized particles to pass through them. Typically the pore size is only 2–7Å, and only 2% or 3% of the membrane is devoted to these pores. As the pressure rises on one side of the membrane, particles that are almost the same size as the pores (about 100MW) are forced through these pores. There are larger intercellular pores, or gaps, between the endothelial cells of the capillary walls in most tissues, allowing passage of larger water-soluble compounds from plasma into the extracellular space. The number and size of these interendothelial gaps varies widely: they are absent in the brain due to the tight junctions between cells, ~40Å in most other tissues and larger (70 or 80Å) in the renal glomerulus, allowing molecules of less than 69 000MW to filter into the urine.
Specialized Transport Systems
Substrate-specific carrier proteins allow rapid transport of polar compounds across membranes. Some carrier proteins facilitate diffusion, transporting compounds down a concentration gradient, while others are integrated into an energy-requiring active transport system for transport of substances against a concentration gradient. Xenobiotics bearing structural or charge similarities to nutrients and endogenous substrates can interact with the specific carrier systems, competing with the endogenous substrate for uptake. For example, the active transport system for uracil and other pyrimidine bases is involved in the uptake of the chemotherapeutic agents, 5'–fluorouracil and 5'–bromouracil. Since these systems do not normally function at saturation, this additional uptake usually has little effect on transport of the true substrate.
Absorption Routes
Toxicologically significant routes of absorption are the gastrointestinal tract, the lungs, and the skin. During transport, some chemicals are modified through metabolism and/or binding. Because of this modification, correct modeling of absorption is essential in toxicological evaluations. Although weak acids and neutral compounds can be absorbed by simple diffusion from the acid stomach, the small intestine is the major site for absorption of xenobiotics from the gastrointestinal tract. Because of the large surface area, the rapid blood flow, and the thin alveolar wall, pulmonary absorption is a rapid and effective route of uptake for gases, volatile compounds, and even some small particulates. Ionizable compounds are absorbed rapidly across the alveolar wall by passive diffusion. For compounds that are relatively poorly water soluble, such as ethylene, uptake is limited by blood flow. Metals do not accumulate in the lungs, but pass directly into plasma so that metal absorption is many times greater in the lungs than in the intestine. The skin is an excellent barrier to all but highly lipid-soluble compounds, such as solvents. However, if the keratinized epidermal layer is removed by abrasion or hydrated by soaking the skin for a prolonged period of time, absorption is greatly increased.
DISTRIBUTION
Volume of Distribution
Body water may be divided into three compartments: the vascular, extracellular, and intracellular spaces. To pass from plasma to extracellular fluid, a compound must be either lipid soluble for diffusion across the endothelial membrane, or sufficiently small to pass through an interendothelial pore. To pass on from the extra– to the intracellular space, a compound must either diffuse or pass through the very much smaller pores of the plasma membrane. With no further refinements, the volume of distribution of a compound would be either 3, 12, or 41 liters in the average adult male, depending on whether distribution was limited to the vascular space alone, the vascular and extracellular spaces, or freely diffusible throughout total body water, respectively.
Two factors serve to add complexity to this distribution pattern. First, excretion is continuous, so that after an initial distribution period of a few minutes, even compounds totally confined to the plasma compartment slowly disappear as they are excreted from the body. Second, very few compounds are evenly distributed within each compartment. This simple three-compartment model must therefore be refined to contain multiple compartments depending on: (1) variation in capillary interendothelial pore size, from very large in the liver to almost absent in the brain; (2) presence of transport systems that permit organ-specific concentration of toxic compounds, such as uptake of iodine in the thyroid; and (3) presence of intracellular storage sinks which shift the equilibrium toward the storage organ, for example, the uptake of fluoride, lead, or strontium into the hydroxyapatite lattice of bone.
Barriers to Distribution
Blood–Brain Barrier
The historical concept of an impenetrable blood–brain barrier is no longer valid. Although water-soluble compounds are effectively excluded, lipid-soluble substances can pass freely across this barrier to concentrate in the fatty nervous tissue. Exclusion of polar substances depends on the fact that junctions between the capillary endothelial cells are far tighter in the brain than in the rest of the body, eliminating interendothelial pores. Astrocyte end feet tightly abut the endothelium, so that a compound must pass through, rather than around, two extra cell layers to pass into the cerebrospinal fluid. Furthermore, active transport systems similar to those found in kidney serve to transport organic acids and bases out of the brain. The blood–brain barrier is undeveloped in immature animals, and develops incompletely in certain areas of the brain, such as the olfactory bulbs. Somewhat similar to the blood–brain barrier is the blood–testis barrier, protecting the male gamete from many xenobiotics, but there is no known corresponding barrier protecting the female gamete.
Placental Barrier
Lipid-soluble xenobiotics freely diffuse from maternal to fetal blood, and thus to the fetus. The less lipid-soluble a compound, the more effectively it is excluded by the placenta. This barrier is equally effective from either direction; therefore any fetal metabolism of a xenobiotic to a more polar metabolite would tend to trap the metabolite in the fetus. Fortunately, most drug-metabolizing systems develop after birth, so that this particular event is avoided.
BIOTRANSFORMATION
Biotransformation, or metabolism, of a xenobiotic can dramatically alter its distribution and action, leading to detoxification and excretion, or to bioactivation and toxicity. Compounds that are so physically similar to an endogenous compound that they enter the body via its active transport mechanism may also share its sites for biochemical action and its route of metabolism, leading to eventual catabolism and excretion. For xenobiotics entering by diffusion, several organs, particularly the liver, contain enzymes with very broad substrate specificity that will metabolize a wide variety of lipid-soluble compounds. Biotransformation to a more water-soluble product usually enhances excretion, decreasing the likelihood of accumulation to toxic levels. However, these same enzymes can bioactivate a number of xenobiotics to reactive intermediates, producing cytotoxicity or carcinogenicity.
Biotransformation has traditionally been divided into two phases. Phase I metabolism is degradative, involving oxidative, reductive, and hydrolytic reactions that cleave substrate molecules. Products may be more or less toxic than the parent compound. Phase II metabolism is synthetic, involving conjugation or addition of xenobiotics to endogenous molecules. While traditionally phase II metabolites have been considered as almost invariably nontoxic, exceptions are growing with our increasing knowledge base. Frequently phase I metabolism produces a suitable site on the metabolized molecule to allow phase II conjugation to occur. For example, benzene is not a substrate for any phase II reaction, but can undergo phase I oxidation to phenol. Phenol can undergo phase II glucuronidation, forming phenol-O-glucuronide, which is excreted.
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Excerpted from Fundamentals of Toxicologic Pathology by Wanda M. Haschek Colin G. Rousseaux Matthew A. Wallig Copyright © 2010 by Elsevier Inc. . Excerpted by permission of Academic Press. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
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