Toxicology Tutor II is the second of three toxicology tutorials being produced by the Toxicology and Environmental Health Information Program of the National




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Tissue affinity determines the degree of concentration of a toxicant.  In fact, some tissues have a higher affinity for specific chemicals and will accumulate a toxicant in great concentrations in spite of a rather low flow of blood.  For example, adipose tissue, which has a meager blood supply, concentrates lipid-soluble toxicants.  Once deposited in these storage tissues, toxicants may remain for long periods of time, due to their solubility in the tissue and the relatively low blood flow.

During distribution, the passage of toxicants from capillaries into various tissues or organs is not uniform.  Structural barriers exist that restrict entrance of toxicants into certain organs or tissues.  The primary barriers are those of the brain, placenta, and testes.

The blood-brain barrier protects the brain from most toxicants.  Specialized cells called astrocytes possess many small branches, which form a barrier between the capillary endothelium and the neurons of the brain.  Lipids in the astrocyte cell walls and very tight junctions between adjacent endothelial cells limit the passage of water-soluble molecules.  The blood-brain barrier is not totally impenetrable, but slows down the rate at which toxicants cross into brain tissue while allowing essential nutrients, including oxygen, to pass through.

The placental barrier protects the developing and sensitive fetus from most toxicants distributed in the maternal circulation.  This barrier consists of several cell layers between the maternal and fetal circulatory vessels in the placenta.  Lipids in the cell membranes limit the diffusion of water-soluble toxicants.  However, nutrients, gases, and wastes of the developing fetus can pass through the placental barrier.  As in the case of the blood-brain barrier, the placental barrier is not totally impenetrable but effectively slows down the diffusion of most toxicants from the mother into the fetus.


Storage Sites

Storage of toxicants in body tissues sometimes occurs. Initially, when a toxicant enters the blood plasma, it may be bound to plasma proteins.  This is a form of storage since the toxicant, while bound to the protein, does not contribute to the chemical's toxic potential. Albumin is the most abundant plasma protein that binds toxicants.  Normally, the toxicant is only bound to the albumen for a relatively short time.

The primary sites for toxicant storage are adipose tissue, bone, liver and kidneys.  Lipid-soluble toxicants are often stored in adipose tissues.  Adipose tissue is located in several areas of the body but mainly in subcutaneous tissue.  Lipid-soluble toxicants can be deposited along with triglycerides in adipose tissues.  The lipids are in a continual exchange with blood and thus the toxicant may be mobilized into the blood for further distribution and elimination, or redeposited in other adipose tissue cells.

Another major site for storage is bone.  Bone is composed of proteins and the mineral salt hydroxyapatite.  Bone contains a sparse blood supply but is a live organ.  During the normal processes that form bone, calcium and hydroxyl ions are incorporated into the hydroxyapatite-calcium matrix.  Several chemicals, primarily elements, follow the same kinetics as calcium and hydroxyl ions and therefore can be substituted for them in the bone matrix.  For example, strontium (Sr) or lead (Pb) may be substituted for calcium (Ca), and fluoride (F-) may be substituted for hydroxyl (OH-) ions.  Bone is continually being remodeled under normal conditions.  Calcium and other minerals are continually being resorbed and replaced, on the average about every 10 years.  Thus, any toxicants stored in the matrix will eventually be released to reenter the circulatory system.

The liver is a storage site for some toxicants.  It has a large blood flow and its hepatocytes (i.e., liver cells) contain proteins that bind to some chemicals, including toxicants.  As with the liver, the kidneys have a high blood flow, which preferentially exposes these organs to toxicants in high concentrations.  Storage in the kidneys is associated primarily with the cells of the nephron (the functional unit for urine formation).




Introduction

Biotransformation is the process whereby a substance is changed from one chemical to another (transformed) by a chemical reaction within the body.  Metabolism or metabolic transformations are terms frequently used for the biotransformation process.  However, metabolism is sometimes not specific for the transformation process but may include other phases of toxicokinetics.

Biotransformation is vital to survival in that it transforms absorbed nutrients (food, oxygen, etc.) into substances required for normal body functions.  For some pharmaceuticals, it is a metabolite that is therapeutic and not the absorbed drug.  For example, phenoxybenzamine (Dibenzyline®), a drug given to relieve hypertension, is biotransformed into a metabolite, which is the active agent.  Biotransformation also serves as an important defense mechanism in that toxic xenobiotics and body wastes are converted into less harmful substances and substances that can be excreted from the body.

If you recall, toxicants that are lipophilic, non-polar, and of low molecular weight are readily absorbed through the cell membranes of the skin, GI tract, and lung.  These same chemical and physical properties control the distribution of a chemical throughout the body and it's penetration into tissue cells.  Lipophilic toxicants are hard for the body to eliminate and can accumulate to hazardous levels.  However, most lipophilic toxicants can be transformed into hydrophilic metabolites that are less likely to pass through membranes of critical cells.  Hydrophilic chemicals are easier for the body to eliminate than lipophilic substances.  Biotransformation is thus a key body defense mechanism.

Fortunately, the human body has a well-developed capacity to biotransform most xenobiotics as well as body wastes.  An example of a body waste that must be eliminated is hemoglobin, the oxygen-carrying iron-protein complex in red blood cells.  Hemoglobin is released during the normal destruction of red blood cells.  Under normal conditions hemoglobin is initially biotransformed to bilirubin, one of a number of hemoglobin metabolites.  Bilirubin is toxic to the brain of newborns and, if present in high concentrations, may cause irreversible brain injury.  Biotransformation of the lipophilic bilirubin molecule in the liver results in the production of water-soluble (hydrophilic) metabolites excreted into bile and eliminated via the feces.

The biotransformation process is not perfect.  When biotransformation results in metabolites of lower toxicity, the process is known as detoxification.  In many cases, however, the metabolites are more toxic than the parent substance.  This is known as bioactivation.  Occasionally, biotransformation can produce an unusually reactive metabolite that may interact with cellular macromolecules (e.g., DNA).  This can lead to a very serious health effect, for example, cancer or birth defects.  An example is the biotransformation of vinyl chloride to vinyl chloride epoxide, which covalently binds to DNA and RNA, a step leading to cancer of the liver.


Chemical Reactions

Chemical reactions are continually taking place in the body.  They are a normal aspect of life, participating in the building up of new tissue, tearing down of old tissue, conversion of food to energy, disposal of waste materials, and elimination of toxic xenobiotics.  Within the body is a magnificent assembly of chemical reactions, which is well orchestrated and called upon as needed.  Most of these chemical reactions occur at significant rates only because specific proteins, known as enzymes, are present to catalyze them, that is, accelerate the reaction.  A catalyst is a substance that can accelerate a chemical reaction of another substance without itself undergoing a permanent chemical change.

Enzymes are the catalysts for nearly all biochemical reactions in the body.  Without these enzymes, essential biotransformation reactions would take place slowly or not at all, causing major health problems.  An example is the inability of persons that have phenylketonuria (PKU) to use the artificial sweetener, aspartame (in Equal®).  Aspartame is basically phenylalanine, a natural constituent of most protein-containing foods.  Some persons are born with a genetic condition in which the enzyme that can biotransform phenylalanine to tyrosine (another amino acid), is defective.  As the result, phenylalanine can build up in the body and cause severe mental retardation.  Babies are routinely checked at birth for PKU. If they have PKU, they must be given a special diet to restrict the intake of phenylalanine in infancy and childhood.

These enzymatic reactions are not always simple biochemical reactions.  Some enzymes require the presence of cofactors or co-enzymes in addition to the substrate (the substance to be catalyzed) before their catalytic activity can be exerted.  These co-factors exist as a normal component in most cells and are frequently involved in common reactions to convert nutrients into energy (Vitamins are an example of co-factors).  It is the drug or chemical transforming enzymes that hold the key to xenobiotic transformation.  The relationship of substrate, enzyme, co-enzyme, and transformed product is illustrated below:



Most biotransforming enzymes are high molecular weight proteins, composed of chains of amino acids linked together by peptide bonds.  A wide variety of biotransforming enzymes exist.  Most enzymes will catalyze the reaction of only a few substrates, meaning that they have high "specificity".  Specificity is a function of the enzyme's structure and its catalytic sites.  While an enzyme may encounter many different chemicals, only those chemicals (substrates) that fit within the enzymes convoluted structure and spatial arrangement will be locked on and affected.  This is sometimes referred to as the "lock and key" relationship.  As shown in the diagram, when a substrate fits into the enzyme's structure, an enzyme-substrate complex can be formed.  This allows the enzyme to react with the substrate with the result that two different products are formed.  If the substrate does not fit into the enzyme, no complex will be formed and thus no reaction can occur.




The array of enzymes range from those that have absolute specificity to those that have broad and overlapping specificity.  In general, there are three main types of specificity:




For example, formaldehyde dehydrogenase has absolute specificity since it catalyzes only the reaction for formaldehyde.  Acetylcholinesterase has absolute specificity for biotransforming the neurotransmitting chemical, acetylcholine.  Alcohol dehydrogenase has group specificity since it can biotransform several different alcohols, including methanol and ethanol.  N-oxidation can catalyze a reaction of a nitrogen bond, replacing the nitrogen with oxygen.

The names assigned to enzymes may seem confusing at first.  However, except for some of the originally studied enzymes (such as pepsin and trypsin), a convention has been adopted to name enzymes.  Enzyme names end in "ase" and usually combine the substrate acted on and the type of reaction catalyzed.  For example, alcohol dehydrogenase is an enzyme that biotransforms alcohols by the removal of a hydrogen.  The result is a completely different chemical, an aldehyde or ketone.

The biotransformation of ethyl alcohol to acetaldehyde is depicted below:




ADH = alcohol dehydrogenase, a specific catalyzing enzyme
NAD = nicotinamide adenine dinucleotide, a common cellular reducing agent

By now you know that the transformation of a specific xenobiotic can be either beneficial or harmful, and perhaps both depending on the dose and circumstances.  A good example is the biotransformation of acetaminophen (Tylenol®), a commonly used drug to reduce pain and fever.  When the prescribed doses are taken, the desired therapeutic response is observed with little or no toxicity.  However, when excessive doses of acetaminophen are taken, hepatotoxicity can occur.  This is because acetaminophen normally undergoes rapid biotransformation with the metabolites quickly eliminated in the urine and feces.

At high doses, the normal level of enzymes may be depleted and the acetaminophen is available to undergo reaction by an additional biosynthetic pathway, which produces a reactive metabolite that is toxic to the liver.  For this reason, a user of Tylenol® is warned not to take the prescribed dose more frequently than every 4-6 hours and not to consume more than four doses within a 24-hour period.  Biotransforming enzymes, like most other biochemicals, are available in a normal amount and in some situations can be "used up" at a rate that exceeds the bodies ability to replenish them.  This illustrates the frequently used phrase, the "Dose Makes the Poison."

Biotransformation reactions are categorized not only by the nature of their reactions, e.g., oxidation, but also by the normal sequence with which they tend to react with a xenobiotic.  They are usually classified as Phase I and Phase II reactions.  Phase I reactions are generally reactions which modify the chemical by adding a functional structure.  This allows the substance to "fit" into the Phase II enzyme so that it can become conjugated (joined together) with another substance.  Phase II reactions consist of those enzymatic reactions that conjugate the modified xenobiotic with another substance. The conjugated products are larger molecules than the substrate and generally polar in nature (water-soluble).  Thus, they can be readily excreted from the body.  Conjugated compounds also have poor ability to cross cell membranes.

In some cases, the xenobiotic already has a functional group that can be conjugated and the xenobiotic can be biotransformed by a Phase II reaction without going through a Phase I reaction.  A good example is phenol that can be directly conjugated into a metabolite that can then be excreted. The biotransformation of benzene requires both Phase I and Phase II reactions.  As illustrated below, benzene is biotransformed initially to phenol by a Phase I reaction (oxidation).  Phenol has the functional hydroxyl group that is then conjugated by a Phase II reaction (sulphation) to phenyl sulfate.




The major transformation reactions for xenobiotics are listed below:




Phase I Reactions

Phase I biotransformation reactions are simple reactions as compared to Phase II reactions.  In Phase I reactions, a small polar group (containing both positive and negative charges) is either exposed on the toxicant or added to the toxicant.  The three main Phase I reactions are oxidation, reduction, and hydrolysis.
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