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Noninvasive liver tests are used to evalu- ate liver structure and function. Typically three types of tests are done. The first in- volves testing blood serum (i.e., the non- cellular portion) for particular enzymes known to be present at specific levels when the liver is functioning properly, but that may be elevated in a damaged liver due to their release into the blood from damaged hepatocytes.

The second type of test, again per- formed on blood, examines liver function for its ability to remove routinely encoun- tered substances (e.g., bilirubin) or intro- duced substances (e.g., dyes) from the blood. Since the liver is responsible for producing most of the factors involved in the cascading sequence of reactions needed to produce a “fibrin clot,” the time for clot formation can be examined as an indicator of liver function.

A third type of test, the liver scan, is used to examine both liver anatomy (e.g., size) and function (e.g., flow of blood and bile). This nuclear test is performed by intrave- nously injecting a radiopharmaceutical, a radioactive chemical used in diagnostics. Pictures using noninvasive radioactive imaging techniques are then taken to

Target Organ Toxicity 91

Figure 7–2. Structure of a liver lobule. (From D.W.Fawcett, Bloom and Fawcett, A

detect the radiopharmaceutical as it circu- lates through the liver.

Nephrotoxicity

Introduction

Nephrotoxicity refers to the toxic effects in the kidney. Remember, three processes occurring in the kidney, glomerular filtra- tion, tubular reabsorption, and tubular secretion, are responsible for the produc- tion of urine. Nephrotoxins are known to influence each of these processes.

Toxicity Mechanisms

During filtration, two toxic responses may be manifest. First, due to the large vol- ume of filtrate formed at the interface of the vascular glomerulus and Bowman’s capsule, toxicants may accumulate in this anatomical region of the nephron. Second, this may in turn increase or decrease the rate of filtration or alter characteristics of the glomerular apparatus (the filter). If the glomerulus is made more porous, or less selective, substances normally excluded by the filter will be able to cross and enter the filtrate.

Other nephrotoxicity mechanisms af- fect both the qualitative and quantitative aspects of the reabsorptive process. The proximal tubule is responsible for the se- lective reabsorption of most of the salts and water present in the filtrate. All amino acids and glucose are reabsorbed and re- turned to the blood in this region. Any changes induced by toxicants or their metabolites in the characteristics of the cell membranes that form the tubule can

profoundly affect the reabsorptive proc- ess.

Tubular secretion, the third and last process of urine formation, is responsible for the active transport of substances from the blood (e.g., H+_{, K}+_{, xenobiotics) into}

the urine. Again, when toxicants or their metabolites alter these transport mecha- nisms, the nephron is unable to function properly and nephrotoxicity may result.

Examples

The pathologies associated with nephro- toxicity are dependent on the anatomical region of the nephron affected by the toxi- cant. Two major responses may be ob- served when the glomerular filtration ap- paratus is injured: nephrotic syndrome and nephritic syndrome. Although the pa- thologies for each are complex, nephrotic syndrome is usually characterized by heavy proteinuria (i.e., presence of pro- tein in the urine), whereas nephritic syn- drome is typically characterized by hema- turia (i.e., presence of blood cells in the urine). Some xenobiotics, such as lead and heroin, are linked to nephrotic syndrome, often resulting in heavy proteinuria.

The selectivity of the glomerular filter can be altered by exposure to xenobiotics. In contrast to increased permeability to albumin resulting from exposure to puro- mycin (an antibiotic), two other antibiot- ics—gentamycin and kanamycin—de-

crease the rate of glomerular filtration.

As the glomerular filtrate flows through the nephron, renal tubules may be exposed to high concentrations of filtered toxicants or their metabolites. Damage to the epi- thelial cells that line the tubules is respon- sible for producing acute tubular necrosis

Target Organ Toxicity 93 (ATN). Heavy metals, antibiotics, and or-

ganic solvents are known to cause ATN. Tubular reabsorption is affected by cad- mium (Cd), lead (Pb), and mercury (Hg). Up to the age of 50, Cd normally accumu- lates in the human kidney—in fact, about 10 times as much Cd accumulates in the kidney as in the liver. Cadmium is capable of producing glycosuria (loss of glucose in the urine) and aminoaciduria (loss of amino acids in the urine). Lead inhibits the reabsorption of glucose and amino acids in the proximal tubule, also leading to gly- cosuria and aminoaciduria. Kidney failure may result from exposure to inorganic mercury (Hg2+_{), a powerful tubular}

nephrotoxin. When oliguria (little urine) or anuria (no urine) is formed, the buildup of toxic wastes in the body can lead to death.

Obstructive uropathies result when the flow of urine is prevented either by intratubular or extratubular pathologies. Ethylene glycol, a commonly used anti- freeze or coolant, is metabolized by the body to calcium oxalate. This insoluble salt accumulates in the proximal tubule, both in the lumen and in the epithelial cells lin- ing the lumen, forming an intratubular obstruction to the normal flow of urine.

Evaluating Nephrotoxicity

A number of quantitative and qualitative tests are used to evaluate kidney function. Glomerular filtration rate (GFR) is defined as the amount of glomerular filtrate (mL) per unit of time (min). GFR can be deter- mined by intravenously administering inu- lin, a fructose polymer (MW=5,200). This sugar polymer is readily distributed in the blood, does not become bound to plasma

proteins, is not metabolized or stored, ef- fortlessly enters the glomerular filtrate, and is not reabsorbed or secreted by the nephron. On entering the glomerular fil- trate, inulin becomes a permanent com- ponent of urine. By measuring the amount of inulin present in plasma (PI) and urine

(UI), and urine volume (V) after a specific

interval of time, the inulin clearance (CI)

can be used to estimate GFR by the fol- lowing formula:

GFR!(UI) (V)/PI=CI

Typical values have been inserted into this formula to show its usefulness in deter- mining normal kidney function as related to glomerular filtration rates:

GFR!(30 mg/mL) (1.25 mL/min)/ 0.3 mg/mL=125 mL/min When nephrotoxicity affects the glomeru- lar filtration apparatus, as may be evi- denced by a decrease in the normal GFR of 125 mL/min, secondary consequences affecting toxicokinetics are likely to oc- cur. For example, a decrease in GFR may result in a decrease in urinary elimination or “clearance” of a toxicant or its metabo- lites. This would increase the T1/2 and

could lead to toxicity involving other organs.

The organic acid PAH (p-aminohippuric acid) is used to evaluate kidney function. Readily filtered, PAH is actively secreted into the urine. It is almost completely “cleared” from blood plasma during one pass through the kidneys—so much so, that PAH clearance is used to estimate the rate of plasma flow through the kidneys. To- gether, inulin and PAH studies provide in- formation about glomerular filtration and tubular secretion.

Two other indicators of kidney func- tion are blood urea nitrogen (BUN) and creatinine. Urea (a potential endogenous toxicant formed from the catabolism of proteins) and creatinine (a product of muscle metabolism) are distributed in the blood. In adults, normally functioning kidneys will eliminate urea (25 g/day) and creatinine (1.8 g/day) into urine. Elevated serum BUN and creatinine levels are in- dicative of kidney dysfunction.

Neurotoxicity

Introduction

The nervous system is divided into the cen- tral nervous system (CNS) and peripheral nervous system (PNS). The CNS includes the brain and spinal cord, which function to process information and provide memory. The PNS contains peripheral nerves that are involved with sensory and motor control functions.

Neurons, more than a billion of them, are the characteristic cells found in both the CNS and PNS. These cells gather in- formation (i.e., sensory), process informa- tion, provide memory, and initiate appro- priate responses (i.e., motor). Neurons are composed of three cellular regions: the cell body, dendrites, and axon. A nerve in the PNS is a collection of individual motor or sensory neurons.

Additional support cells in the CNS, termed glial cells, provide a structural framework and transport of nutrients (astrocytes), myelin production (oligodendrocytes), and immune function (microglia). The oligodendrocytes (CNS) and Schwann cells (PNS) are responsible for the production of myelin, a lipid-rich

“cell membrane wrapping” around axons. Myelin functions to insulate the axon, en- hancing the velocity of axonal conduction. Neurons, either sensory or motor, are linked together to form a communication network. Two different processes are re- sponsible for the propagation of a com- munication along a neuronal path. The first process ensures that a signal is “elec- trically” transmitted along the length of each neuron’s axon, while the second “chemically” propagates the signal from one neuron to the next.

Neurotoxins are known to alter neurons in both the CNS and PNS, as well as the glial support cells in the CNS. Much of our current understanding of the nervous sys- tem’s structure and function has resulted from the experimental use of neuro- toxins—particularly neurotoxins affecting cell membrane proteins that function in cell transport and as membrane receptors.

Toxicity Mechanisms

Neurotoxins interfere with the communi- cation ability of neurons, impeding recep- tor or motor neuron signaling and CNS functioning. Neurons are able to propagate a signal due to an electrical gradient that exists between the inside and outside of the axonal cell membrane. The gradient is cre- ated by Na+_/K+ _{pumps in the cell mem-}

brane. These pumps actively transport Na+

to the outside of the cell and K+ _{to the in-}

side of the cell, creating a potential differ- ence of about—70 mV (millivolts) across the axonal cell membrane.

Within a single neuron, signal propaga- tion occurs when the electrical wave of depolarization runs the entire length of the axon. Depolarization results when passive

Target Organ Toxicity 95 transport channels open to permit Na+ _to

rapidly enter the cell membrane, followed almost instantaneously by additional pas- sive channels that open to allow K+ _{to exit.}

When passive or active transport mecha- nisms are slowed, blocked, or otherwise impaired, or if the membrane “leaks” ex- cessively, the potential difference cannot be maintained and the neuron will be unable to propagate a signal down the length of the axon.

When signals reach the distal axonal region, a second process called synaptic transmission is initiated. Synaptic transmis- sion is responsible for propagation of the signal to the next neuron. In this process a neurotransmitter (chemical messenger), is released from the distal region (i.e., presy- naptic neuron). Once released (i.e., exocytosis of vesicles), the neurotransmit- ter moves across the synaptic cleft (a mi- croscopically small space) to bind to receptors on the membrane surface of the postsynaptic neuron.

If sufficient neurotransmitters bind to the postsynaptic membrane receptors, the postsynaptic neuron will depolarize and the electrical wave will be propagated down the axon of the next neuron. Synaptic transmission involves a chemi- cal mode of transmission rather than the electrical gradient responsible for propa- gating the signal in the axon.

Neurotoxins may bind to postsynaptic receptors, blocking synaptic transmission. Following synaptic transmission, neurotoxins may act to inhibit the “re- moval,” or degradation, of the recently released neurotransmitters, permitting continued synaptic transmission that may be sufficient to repeatedly depolarize the postsynaptic neuron.

Examples

Neurotoxicity results when toxicants in- terrupt the normal mechanisms of neu- ronal communication. Batrachotoxin, se- creted by frogs, destroys the electrical gra- dient by increasing the Na+ _permeability

of the axonal cell membrane. Ethanol de- presses CNS function by (1) inhibiting or stimulating a variety of transport chan- nels and (2) increasing membrane fluid- ity by altering the packing of molecules within the membrane. Both processes act to depolarize the neuron, thereby decreas- ing signal transmission.

The insecticide DDT increases mem- brane permeability to Na+ _{in the presyn-}

aptic region, which leads to continual signaling. Other insecticides (e.g., malathion, diazinon) prevent the break- down of acetylcholine, a neurotransmitter, by binding to cholinesterase, an enzyme responsible for catabolism.

Tetrodotoxin, found in puffer fish, blocks Na+ _{channels. Botulin toxin, a}

bacteriotoxin, prevents the release of the neurotransmitter acetylcholine. Curare, a phytotoxin, is a neuromuscular blocking agent that prevents a motor neuron from signaling a muscle cell by blocking ace- tylcholine receptors on muscle cells.

A number of neurotoxins (e.g., hexachlorophene and lead) damage the myelin sheath. This loss of insulation re- sults in signal “short circuiting” between adjacent neurons and slower neuronal transmission velocities.