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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Oxidation is a chemical reaction in which a substrate loses electrons.  There are a number of reactions that can achieve the removal of electrons from the substrate.  Addition of oxygen was the first of these reactions discovered and thus the reaction was named oxidation.  However, many of the oxidizing reactions do not involve oxygen.  The simplest type of oxidation reaction is dehydrogenation, that is the removal of hydrogen from the molecule.  Another example of oxidation is electron transfer that consists simply of the transfer of an electron from the substrate.

Examples of these types of oxidizing reactions are illustrated below:










The specific oxidizing reactions and oxidizing enzymes are numerous and several textbooks are devoted to this subject.  Most of the reactions are self-evident from the name of the reaction or enzyme involved.  Listed are several of these oxidizing reactions.



  • alcohol dehydrogenation

  • aldehyde dehydrogenation

  • alkyl/acyclic hydroxylation

  • aromatic hydroxylation

  • deamination

  • desulfuration

  • N-dealkylation

  • N-hydroxylation

  • N-oxidation

  • O-dealkylation

  • sulphoxidation


Reduction is a chemical reaction in which the substrate gains electrons.  Reductions are most likely to occur with xenobiotics in which oxygen content is low.  Reductions can occur across nitrogen-nitrogen double bonds (azo reduction) or on nitro groups (NO2). Frequently, the resulting amino compounds are oxidized forming toxic metabolites.  Some chemicals such as carbon tetrachloride can be reduced to free radicals, which are quite reactive with biological tissues.  Thus, reduction reactions frequently result in activation of a xenobiotic rather than detoxification.  An example of a reduction reaction in which the nitro group is reduced is illustrated below:



There are fewer specific reduction reactions than oxidizing reactions.  The nature of these reactions is also self-evident from their name.  Listed are several of the reducing reactions.



  • azo reduction

  • dehalogenation

  • disulfide reduction

  • nitro reduction

  • N-oxide reduction

  • sulfoxide reduction



Hydrolysis is a chemical reaction in which the addition of water splits the toxicant into two fragments or smaller molecules.  The hydroxyl group (OH-) is incorporated into one fragment and the hydrogen atom is incorporated into the other.  Larger chemicals such as esters, amines, hydrazines, and carbamates are generally biotransformed by hydrolysis.  The example of the biotransformation of procaine (local anesthetic) which is hydrolyzed to two smaller chemicals is illustrated below:




Toxicants that have undergone Phase I biotransformation are converted to metabolites that are sufficiently ionized, or hydrophilic, to be either eliminated from the body without further biotransformation or converted to an intermediate metabolite that is ready for Phase II biotransformation.  The intermediates from Phase I transformations may be pharmacologically more effective and in many cases more toxic than the parent xenobiotic.

Phase II Reactions

A xenobiotic that has undergone a Phase I reaction is now a new intermediate metabolite that contains a reactive chemical group, e.g., hydroxyl (-OH), amino (-NH2), and carboxyl (-COOH).  Many of these intermediate metabolites do not possess sufficient hydrophilicity to permit elimination from the body.  These metabolites must undergo additional biotransformation as a Phase II reaction.

Phase II reactions are conjugation reactions, that is, a molecule normally present in the body is added to the reactive site of the Phase I metabolite.  The result is a conjugated metabolite that is more water-soluble than the original xenobiotic or Phase I metabolite.  Usually the Phase II metabolite is quite hydrophilic and can be readily eliminated from the body.  The primary Phase II reactions are:

  • glucuronide conjugation - most important reaction

  • sulfate conjugation - important reaction

  • acetylation

  • amino acid conjugation

  • glutathione conjugation

  • methylation



Glucuronide conjugation is one of the most important and common Phase II reactions. One of the most popular molecules added directly to the toxicant or its phase I metabolite is glucuronic acid, a molecule derived from glucose, a common carbohydrate (sugar) that is the primary source of energy for cells. The sites of glucuronidation reactions are substrates having an oxygen, nitrogen, or sulfur bond.  This includes a wide array of xenobiotics as well as endogenous substances, such as bilirubin, steroid hormones and thyroid hormones.  Glucuronidation is a high-capacity pathway for xenobiotic conjugation.  Glucuronide conjugation usually decreases toxicity.  Although there are some notable exceptions, for example, the production of carcinogenic substances.  The glucuronide conjugates are generally quite hydrophilic and are excreted by the kidney or bile, depending on the size of the conjugate.  The glucuronide conjugation of aniline is illustrated below:




Sulfate conjugation is another important Phase II reaction that occurs with many xenobiotics. In general, sulfation decreases the toxicity of xenobiotics.  Unlike glucuronic acid conjugates that are often eliminated in the bile, the highly polar sulfate conjugates are readily secreted in the urine.  In general, sulfation is a low-capacity pathway for xenobiotic conjugation.  Often glucuronidation or sulfation can conjugate the same xenobiotics.


Biotransformation Sites

Biotransforming enzymes are widely distributed throughout the body.  However, the liver is the primary biotransforming organ due to its large size and high concentration of biotransforming enzymes.  The kidneys and lungs are next with 10-30% of the liver's capacity.  A low capacity exists in the skin, intestines, testes, and placenta.  Since the liver is the primary site for biotransformation, it is also potentially quite vulnerable to the toxic action of a xenobiotic that is activated to a more toxic compound.

Within the liver cell, the primary subcellular components that contain the transforming enzymes are the microsomes (small vesicles) of the endoplasmic reticulum and the soluble fraction of the cytoplasm (cytosol).  The mitochondria, nuclei, and lysosomes contain a small level of transforming activity.

Microsomal enzymes are associated with most Phase I reactions.  Glucuronidation enzymes, however, are contained in microsomes.  Cytosolic enzymes are non-membrane-bound and occur free within the cytoplasm.  They are generally associated with Phase II reactions, although some oxidation and reduction enzymes are contained in the cytosol.  The most important enzyme system involved in Phase I reactions it the cytochrome P-450 enzyme system.  This system is frequently referred to as the "mixed function oxidase (MFO) " system.  It is found in microsomes and is responsible for oxidation reactions of a wide array of chemicals.

The fact that the liver biotransforms most xenobiotics and that it receives blood directly from the gastrointestinal tract renders it particularly susceptible to damage by ingested toxicants.  Blood leaving the gastrointestinal tract does not directly flow into the general circulatory system.  Instead, it flows into the liver first via the portal vein.  This is known as the "first pass" phenomena.  Blood leaving the liver is eventually distributed to all other areas of the body; however, much of the absorbed xenobiotic has undergone detoxication or bioactivation.  Thus, the liver may have removed most of the potentially toxic chemical.  On the other hand, some toxic metabolites are in high concentration in the liver.


Modifiers of Biotransformation

The relative effectiveness of biotransformation depends on several factors, including species, age, gender, genetic variability, nutrition, disease, exposure to other chemicals that can inhibit or induce enzymes, and dose levels.  Differences in species capability to biotransform specific chemicals are well known.  Such differences are normally the basis for selective toxicity, used to develop chemicals effective as pesticides but relatively safe in humans.  For example, malathion in mammals is biotransformed by hydrolysis to relatively safe metabolites, but in insects, it is oxidized to malaoxon, which is lethal to insects.

Safety testing of pharmaceuticals, environmental and occupational substances is conducted with laboratory animals.  Often differences between animal and human biotransformation are not known at the time of initial laboratory testing since information is lacking in humans.  Humans have a higher capacity for glutamine conjugation than laboratory rodents.  Otherwise, the types of enzymes and biotransforming reactions are basically comparable.  For this reason, determination of biotransformation of drugs and other chemicals using laboratory animals is an accepted procedure in safety testing.

Age may affect the efficiency of biotransformation.  In general, human fetuses and neonates (newborns) have limited abilities for xenobiotic biotransformations.  This is due to inherent deficiencies in many, but not all, of the enzymes responsible for catalyzing Phase I and Phase II biotransformations.  While the capacity for biotransformation fluctuates with age in adolescents, by early adulthood the enzyme activities have essentially stabilized.  Biotransformation capability is also decreased in the aged. Gender may influence the efficiency of biotransformation for specific xenobiotics.  This is usually limited to hormone-related differences in the oxidizing cytochrome P-450 enzymes.

Genetic variability in biotransforming capability accounts for most of the large variation among humans.  The Phase II acetylation reaction in particular is influenced by genetic differences in humans.  Some persons are rapid and some are slow acetylators.  The most serious drug-related toxicity occurs in the slow acetylators, often referred to as "slow metabolizers".  With slow acetylators, acetylation is so slow that blood or tissue levels of certain drugs (or Phase I metabolites) exceeds their toxic threshold.

Examples of drugs that build up to toxic levels in slow metabolizers that have specific genetic-related defects in biotransforming enzymes are listed below:



Poor nutrition can have a detrimental effect on biotransforming ability.  This is related to inadequate levels of protein, vitamins, and essential metals.  These deficiencies can decrease the ability to synthesize biotransforming enzymes.  Many diseases can impair an individual's capacity to biotransform xenobiotics.  A good example, is hepatitis (a liver disease), which is well known to reduce hepatic biotransformation to less than half normal capacity.

Enzyme inhibition and enzyme induction can be caused by prior or simultaneous exposure to xenobiotics.  In some situations exposure to a substance will inhibit the biotransformation capacity for another chemical due to inhibition of specific enzymes.  A major mechanism for the inhibition is competition between the two substances for the available oxidizing or conjugating enzymes, that is the presence of one substance uses up the enzyme that is needed to metabolize the second substance.

Enzyme induction is a situation where prior exposure to certain environmental chemicals and drugs results in an enhanced capability for biotransforming a xenobiotic.  The prior exposures stimulate the body to increase the production of some enzymes.  This increased level of enzyme activity results in increased biotransformation of a chemical subsequently absorbed.  Examples of enzyme inducers are alcohol, isoniazid, polycyclic halogenated aromatic hydrocarbons (e.g., dioxin), phenobarbital, and cigarette smoke.  The most commonly induced enzyme reactions involve the cytochrome P-450 enzymes.

Dose level can affect the nature of the biotransformation.  In certain situations, the biotransformation may be quite different at high doses versus that seen at low dose levels.  This contributes to the existence of a dose threshold for toxicity.  The mechanism that causes this dose-related difference in biotransformation usually can be explained by the existence of different biotransformation pathways.  At low doses, a xenobiotic may follow a biotransformation pathway that detoxifies the substance.  However, if the amount of xenobiotic exceeds the specific enzyme capacity, the biotransformation pathway is "saturated".  In that case, it is possible that the level of parent toxin builds up.  In other cases, the xenobiotic may enter a different biotransformation pathway that may result in the production of a toxic metabolite.

An example of a dose-related difference in biotransformation occurs with acetaminophen (Tylenol®).  At normal doses, approximately 96% of acetaminophen is biotransformed to non-toxic metabolites by sulfate and glucuronide conjugation.  At the normal dose, about 4% of the acetaminophen is oxidized to a toxic metabolite; however, that toxic metabolite is conjugated with glutathione and excreted.  With 7-10 times the recommended therapeutic level, the sulphate and glucuronide conjugation pathways become saturated and more of the toxic metabolite is formed.  In addition, the glutathione in the liver may also be depleted so that the toxic metabolite is not detoxified and eliminated.  It can react with liver proteins and cause fatal liver damage.




Introduction

Elimination from the body is very important in determining the potential toxicity of a xenobiotic.  When a toxic xenobiotic (or its metabolites) is rapidly eliminated from the body, it is less likely that they will be able to concentrate in and damage critical cells.  The terms excretion and elimination are frequently used to describe the same process whereby a substance leaves the body.  Elimination, however, is sometimes used in a broader sense and includes the removal of the absorbed xenobiotic by metabolism as well as excretion.  Excretion, as used here, pertains to the elimination or ejection of the xenobiotic and it's metabolites by specific excretory organs.

Except for the lung, polar (hydrophilic) substances have a definite advantage over lipid-soluble toxicants as regards elimination from the body.  Chemicals must again pass through membranes in order to leave the body, and the same chemical and physical properties that governed passage across other membranes applies to excretory organs as well.

Toxicants or their metabolites can be eliminated from the body by several routes.  The main routes of excretion are via urine, feces, and exhaled air.  Thus, the primary organ systems involved in excretion are the urinary system, gastrointestinal system and respiratory system.  A few other avenues for elimination exist but they are relatively unimportant, except in exceptional circumstances.


Urinary Excretion

Elimination of substances by the kidneys into the urine is the primary route of excretion of toxicants.  The primary function of the kidney is the excretion of body wastes and harmful chemicals.  The functional unit of the kidney responsible for excretion is the nephron.  Each kidney contains about one million nephrons.  The nephron has three primary regions that function in the renal excretion process, the glomerulus, proximal tubule, and the distal tubule.  These are identified in the illustrations.



V. C. Scanlon and T. Sanders, Essentials of Anatomy and Physiology, 2nd edition. F. A. Davis, 1995.




V. C. Scanlon and T. Sanders, Essentials of Anatomy and Physiology, 2nd edition. F. A. Davis, 1995.

Three processes are involved in urinary excretion: filtration, secretion, and reabsorption.  Filtration, the first process, takes place in the glomerulus, the very vascular beginning of the nephron.  Approximately one-fourth of the cardiac output circulates through the kidney, the greatest rate of blood flow for any organ.  A considerable amount of the blood plasma filters through the glomerulus into the nephron tubule.  This results from the large amount of blood flow through the glomerulus, the large pores (40 Å) in the glomerular capillaries, and the hydrostatic pressure of the blood.  Small molecules, including water, readily pass through the sieve-like filter into the nephron tubule.  Both lipid soluble and polar substances will pass through the glomerulus into the tubule filtrate.  The amount of filtrate is very large, about 45 gallons/day in an adult human.  About 99% of the water-like filtrate, small molecules, and lipid-soluble substances, are reabsorbed downstream in the nephron tubule.  The urine, as eliminated, is thus only about one percent of the amount of fluid filtrated through the glomerulae into the renal tubules.

Molecules with molecular weights greater than 60,000 (which include large protein molecules and blood cells) cannot pass through the capillary pores and remain in the blood.  If albumen or blood cells are found in urine it is an indication that the glomerulae have been damaged.  Binding to plasma proteins will influence urinary excretion.  Polar substances usually do not bind with the plasma proteins and thus can be filtered out of the blood into the tubule filtrate.  In contrast, substances extensively bound to plasma proteins remain in the blood.
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