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Home , Carboxyhemoglobin, Hormesis, Lipid, Metabolism

180 (2002) 139Á/150 www.elsevier.com/locate/toxicol

Metabolic modulation of monoxide toxicity

Stanley T. Omaye *

Department of and Environmental Toxicology and Health Track, Environmental Sciences and Health Graduate Program, University of Nevada, Reno, NV 89557, USA

Abstract

Carbon monoxide (CO) gas is a of the incomplete combustion of carbon-based fuels and substances. From a public health perspective, CO poisoning may be the cause of more than 50% of fatal poisonings in many industrial countries. The adverse effects of CO poisoning may be more widespread because of unreported situations and delayed neurologic effects, which may be linked to CO exposure. Chronic CO effects that are subtle, such as the adverse effects on vascular diseases, may increase the number of people at risk. The apparent role of CO as an important mediator of signaling is a paradox and may represent an example of , i.e. beneficial effects at low but adverse effects at higher . Nevertheless, because CO can form ligands with () and copper sites, the potential for metabolic intervention is likely. Furthermore, CO-induced oxidative opens the opportunity for modulating the adverse effects of CO with (both - and -soluble compounds) and various factors involved with reducing . However, consideration must be given to the micro-environment in some situations that could potentially create more oxidation and subsequent metabolic damage if the combinations and concentrations of antioxidants are not correct, i.e. pro oxidant effects. Likewise, it is important that we take precautions in the development of adjuvants to use with therapies in CO poisoning. # 2002 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: CO poisoning; Hormesis; CO-induced oxidative stress

1. Introduction 1988; Yang et al., 1998; Varon et al., 1999). CO, a product of incomplete combustion (oxidation) of If the increase in recent years of the use of home carbon compounds, is a toxic gas that is colorless, (CO) detectors is any indication, odorless, and tasteless. Motor vehicles, various the consumer has become more aware of the appliances that use carbon-based fuels, and fire- dangers of CO poisoning. Acute episodes of CO places used for heating homes are the main sources exposure are the leading cause of poisoning in the of CO. and may account for more than 50% There has also been an increase in clinical of fatal poisonings reported in many industrial awareness that a link exists between chronic countries (Cobb and Etzel, 1991; Meredith et al., exposure to CO and the ethology of vascular or cardiovascular diseases (Stern et al., 1988; Klein- man et al., 1989; Sheps et al., 1990; Allred et al., * Tel.: /1-775-784-6447; fax: /1-775-784-6449 E-mail address: [email protected] (S.T. Omaye). 1989). An underpinning supposition is CO derived

0300-483X/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 0 0 - 4 8 3 X ( 0 2 ) 0 0 3 8 7 - 6 140 S.T. Omaye / Toxicology 180 (2002) 139Á/150 from smoke, either from active involved. , such as found in paint strip- or from environmental tobacco smoke exposure pers, or those used for degreasing machinery, can (Mennear, 1993; Freund et al., 1993; Milei et al., form methylene . Methylene chloride va- 1998), may be a critical risk factor for chronic pors are readily absorbed by the into the diseases. Thus, there is certainly a greater sense of circulation and, as shown in Fig. 1, upon reaching public and medical awareness regarding the dan- the can be converted to CO. Methylene gers of CO exposure. chloride can be deposited in fatty during Coincidentally, there has been recent scientific chronic exposures. Individuals who inhale suffi- interest in purported roles of CO in signal cient quantities, may be overcome by CO toxicity transduction, somewhat analogous to the role of some time after exposure due to the slow release of (NO). Overall, we have a good under- methylene chloride from and sub- standing about the physiological response and sequent in the liver to CO. underlying metabolic effects for CO toxicity, and The exhaust from gasoline internal combustion these roles will only be briefly reviewed here (Cobb engines contains between 3 and 7% CO. Emission and Etzel, 1991; Meredith et al., 1988; Yang et al., standards for motor vehicles in the United States 1998; Varon et al., 1999; Penney, 2000). The intent set CO limitation to 0.5%. More than 50% of of this review is to discuss recent findings focused due to CO can be attributed to motor on the physiological and metabolic responses to vehicle exhaust mostly associated with the CO, particularly, with respect to how we might engine in stationary vehicles, in closed garages. better use such knowledge to design ways to Smoke inhalation from all types of fire ranks modulate the toxic response. Such knowledge second as the leading cause of CO poisoning, will enable us to develop efficacious adjuvants in particularly for firefighters. Epidemics of CO treating CO poisoning and better understand the poisoning are more common during the winter role of CO in chronic diseases. months, particularly when power outages occur forcing people to use alternative wood-burning sources for heat. Transient concentrations of CO 2. Environmental sources of CO and magnitude of can be high in tunnels and parking garages due to exposure the accumulation of motor exhaust fumes (Stern et al., 1988). Car exhaust fumes, smoke from fires, gas- An estimated 10 000Á/40 000 people each year powered engines, wood-burning fire places, and will seek medical attention or miss due to CO methylene chloride containing paints are the most poisoning in the United States (Schaplowsky et al., common sources of CO. Some common environ- 1974; Hampson, 1998). Mortality rates between 1 mental CO sources are listed in Table 1.An and 31% have been reported; however, the true improperly vented natural gas heater in a small incidence of CO poisoning is not known, since room can make the air unsafe to breathe within a many non-lethal incidences are not reported. matter of minutes. Cases of CO poisoning have Complete, timely data are often difficult to obtain, occurred outdoors when faulty equipment was particularly for developing countries. A significant number of missed diagnoses may occur because of Table 1 patients’ association of the symptoms with viral Common environmental sources of CO illness or clinical depression. Fortunately, deaths from CO have declined consistently in the United Propane engines Radiant heaters Portable generators Kerosene heaters Gas fireplaces Natural gas States during the past two decades. The decline in appliances Motor vehicle Fires Paint exhaust Hibachi cookers Tobacco smoke Fig. 1. Hepatic conversion of methylene chloride to CO. Methylene chloride (CH2Cl2). S.T. Omaye / Toxicology 180 (2002) 139Á/150 141

CO-related deaths is attributed, in part, to trans- At-risk-populations for CO related health ef- portation-related emission controls, improved fects include: individuals with anemia, hematolo- safety of and heating appliances, and gical disorders, compromised flow, and intensive education to increase consumers’ aware- those with chronic cardiopulmonary diseases, ness of the dangers of CO poisoning (Varon et al., particularly the elderly (Varon et al., 1999; Raub 1999; Raub et al., 2000). et al., 2000). One can reach lethal concentration of CO within 10 min from a motor vehicle by running an automobile in a closed garage. Acute CO toxicity can occur when ambient CO air levels reach 0.1% 3. Endogenous CO formation or 1000 ppm, i.e. unconsciousness, respiratory As red cells age, they are removed from circula- failure, and after 1 h of exposure. Although tion and their heme is degraded. Heme degrada- CO accumulation with chronic exposure does not tion begins with oxidative cleavage of the occur, the anoxia can cause central nervous system between rings A and B, forming the damage. CO exposure is particularly dangerous to green tetrapyrrole, biliverdin, shown in Fig. 2.As pregnant women and to their . Women with shown in Fig. 3, the methenyl bridge carbon increased exposure to CO have reduced blood between porphyrin rings A and B is released as concentrations and an increased ven- CO. is the rate-limiting in tilation rate and are more vulnerable to CO. Fetal the heme catabolic pathway. Subsequently, bili- blood has a greater affinity for CO and the CO to verdin can be reduced to the redÁ/orange . hemoglobin complex, carboxyhemoglobin, can be CO will form a resilient heme ligand and approxi- 10Á/15% higher compared with the mother (Far- mately 1% of hemoglobin’s oxygen binding sites row et al., 1990). The most common source of CO are blocked by CO from endogenous sources, even to the mother is from smoking and may be related in the absence of any air . In contrast to to the reason smoking is a major factor in higher concentration of CO, at 1%, steric condi- increased incidence of stillbirths, premature deliv- tions at the molecular level favors an overall eries, and reduced birth of babies. The reduced affinity of heme for CO compared with avidly bound CO to results in oxygen, permitting the CO to be exhaled slowly. In slow transplacental transport, resulting in fetal CO the situation where mutant hemoglobin Zurich, a level decreases that are much slower than those substitution of Arg for His results in 10% of the occurring in the mother. Thus, causing fetal deaths heme carrying CO. in situations where CO was nonfatal to the The turnover of other contribute mothers. Individuals may be exposed to 400 ppm to CO, such as from , , cyto- of CO from a typical cigarette or about 4% chromes, and . It has been estimated carboxyhemoglobin levels for 5 min smoking that approximately 79% of the CO produced is bouts. A heavy smoker could have carboxyhemo- from the heme of RBCs, including some degraded levels as high as 15%. One study reported cells during erythropoiesis in the bone marrow. Up that cigarette smoke contains 42 000 ppm or 4.2% to 21% of the endogenous CO is derived from the of CO and can significantly elevate the level of carboxyhemoglobin (Abelson, 1967). It has also been reported that nonsmokers exposed to envir- onmental tobacco smoke can have an incremental doubling of their carboxyhemoglobin (normal is about 1%). Incidentally, smokers do show some adaptive increased red-cell volumes and reduced plasma volumes to elevated carboxyhemoglobin levels, a response to chronic smoking. Fig. 2. Heme degradation, sources of endogenous CO. 142 S.T. Omaye / Toxicology 180 (2002) 139Á/150

sensitivity to NO in may be com- pensated for by an induction of heme oxidase, producing bilirubin, an antioxidant and CO as a vasodilator (Siow et al., 1999). Such adaptive responses may contribute to the maintenance of vascular tone in atherosclerotic vessels and com- pensate for diminished NO generation and activ- ity. Such findings imply that CO may promote vascular health at low concentration. Apparent paradoxical affects of CO seem perplexing in terms of defining a mode of action. However, the biphasic effects of CO might be another example of hormesis in action. Hormesis is the phenom- enon whereby a substance has been found to exhibit beneficial effects at a low or very low concentration in contrast to detrimental responses found at a higher concentration (Furst, 1987; Heiby, 1988; Calabrese et al., 1999). The phenom- enon of a response opposite to that which is expected can be observed, is well documented,

and has been referred to as the ‘ArndtÁ/Schulz law’, the ‘reverse effect’ or simply, ‘paradoxical reaction’ (Furst, 1987; Heiby, 1988). Many exam- Fig. 3. Origin of endogenous CO (bolded bond). Methyl (M), ples can be found with agents such as: alcoholic vinyl (V), propionyl (P) and ethyl (E) groups. beverages, gases, barbiturates, some tranquilizers, many , , , degradation of other hemoproteins and other salicylates, and some metals. For ingestion alco- sources. hol, the first dose results in the stimulation of Minor amounts of CO may be derived from the and elevation of body ; process of , such as from but, at a higher dose, respiration is slowed and NADPH-dependent oxidation of microsomal li- body temperature decreases. For ingestion of 3 pids (Nishibayashi et al., 1968), Fe -ascorbate nicotine, there is a transient stimulation of auto- catalyzed oxidation of microsomes (Wolff et al., nomic ganglia at low doses, followed by a persis- 1976), or carbon tetrachloride induced degrada- tent depression of these autonomic ganglia. tion of membrane (Lindstrom et al., 1978). rates are first elevated and then slowed. CO, along with nitric oxide (NO), appear to modulate intracellular cGMP levels, platelet ag- gregation, and smooth muscle relaxation. Overall, 4. Mechanisms of CO toxicity CO has a lower affinity for soluble guanylyl cyclase (a heme ) than NO (Fig. 4). It has 4.1. Hemoglobin been suggested that decreased production or CO diffuses freely in air and does not layer significantly. CO has a significant affinity for all iron- or copper-containing sites and competes with oxygen at these active sites. hemoglobin is a major target site for CO. CO combines with hemoglobin to form carboxyhemo- Fig. 4. Interaction of CO with guanylyl cyclase. globin, a that is incapable of carrying S.T. Omaye / Toxicology 180 (2002) 139Á/150 143 oxygen to tissue sites, resulting in tissue . subsequently binds CO to hemoglobin. A reduc- The binding of CO to hemoglobin is reversible tion in oxygen delivery because of the elevated and, removing an individual from the source of carboxyhemoglobin level, exacerbated by impaired CO will lead to eventual removal of CO from the , which results from hypoxic cardiac body. The CO hemoglobin ligand has an affinity dysfunctions, will impair cellular oxidative meta- 240 times greater than that of oxygen. Also, the bolism, i.e. ischemia. The hypoxia and reduction in CO hemoglobin ligand on any one of the four blood flow allow CO to bind to c oxygen binding sites of hemoglobin results in the oxidase, interfering with at the complex having a greater affinity for oxygen at the mitochondrial level, i.e. aerobic tripho- remaining binding sites. Thus, oxygen bound to sphate synthesis. This disturbance in electron the CO hemoglobin produces a complex that does transport also increases the production of reactive not give oxygen to peripheral body tissue sites. The oxygen species (ROS) and induces oxidative stress. increased affinity for oxygen by the carboxyhe- Because of the continued inhibition of respiration moglobin complex is known as the Haldane effect. by carboxyhemoglobin, production and The Haldane effect causes a leftward shift of the mitochondrial are restored slowly (Hen- oxygen hemoglobin dissociation curve. Not only drik et al., 2000; Penney, 2000). does the oxygenÁ/hemoglobin dissociation curve shift to the left but the curve is distorted from a Much of the late changes associated with CO sigmoidal shape to a hyperbola. In addition, the poisoning is similar to post ischemic reperfusion decreased oxygen delivery becomes sensed at the injuries, including oxidative stress. In rats, allo- central nervous system, resulting in ventilatory purinol prevents the late effects of CO exposure. stimulation and further increased uptake of CO, Likewise, rats made leukopenic do not demon- elevation in carboxyhemoglobin, and eventually strate the late effects of CO poisoning (Miro et al., respiratory alkalosis. Thus, CO is toxic because of 1999; Hendrik et al., 2000; Penney, 2000). its capacity to reduce both the oxygen-carrying capacity and the oxygen-unloading function of the hemoglobin molecule. 4.3. Cytochrome oxidase

4.2. Myoglobin and CO bind to and inhibit cytochrome oxidase (Complex IV)(Fig. 6). The consequence is Other hemeprotein have an affinity for CO (Fig. all components preceding cytochrome oxidase, the 5). Muscle myoglobin has an affinity for CO, terminal electron complex, become reduced; and it which is 40 times greater than that for oxygen. is not possible to pump . Unless immediate Like hemoglobin, CO association with myoglobin intervention occurs, cells respond by switching to will display leftward oxygen dissociation. CO also anaerobic metabolism, resulting in lacticacidosis binds to cardiac myoglobin. Cardiac myoglobin and eventual death. can be used to binds three times more CO than skeletal myoglo- alleviate the inhibition of cytochrome oxidase by bin. A delayed return of CO symptoms has been accepting electrons from described and appears to result when a recurrence (Complex III) permitting Complex I and cyto- of increased carboxyhemoglobin levels, presum- chrome c reductase to pump protons, so that ATP ably due to late release of CO from myoglobin, can continue to be synthesized (Baynes et al., 1999).

Fig. 5. Interaction of CO and hemeproteins with the formation of carboxyhemeproteins. Fig. 6. Interaction of CO with cytochrome oxidase. 144 S.T. Omaye / Toxicology 180 (2002) 139Á/150

4.4. carboxyhemoglobin level that the American Con- ference of Governmental Industrial Hygienists Although the physiologic significance is not suggested as the best estimate of a no effect known, CO can bind to cytochrome P450 hemo- concentration among industrial workers (ACGIH, protein. This relationship was used to study the 1991). It also is a level below 6.3% carboxyhemo- spectroscopic properties of cytochrome P450 en- globin, which noted above(Stern et al., 1988), is zymes. The heme group of such forms a the concentration associated with increased is- strong chromophore with spectroscopic properties chemic heart disease risk in tunnel workers or that are sensitive to the of the ligands 3.9% carboxyhemoglobin found to have an effect bounds, to the iron oxidation state, and the on -induced arrhythmias in patients with protein environment with which the heme is preexisting coronary disease (Sheps et al., associated. 1990). Increases of carboxyhemoglobin levels above 20%, resulting in the patient developing headache, dizziness, confusion and nausea. Pa- 5. Pathophysiology of CO tients with cardiopulmonary problems, such as chronic obstructive pulmonary diseases or angina, Principal manifestation of CO poisoning is may have exacerbated effects at low levels of dyspnea. Earliest signs in mild exposure are carboxyhemoglobin. CO binds with high affinity nausea, vomiting, and dizziness. Moderate expo- to cardiac myoglobin and exhausts cell oxygen sures result in , tachypnea, weakness reserves. Patients may complain of chest pain, and ataxia. More severe CO poisoning results in which can be attributed to cardiac dysrhythmias syncope, seizures, hypotension, coma and death. due to myocardial ischemia. Carboxyhemoglobin The heart is readily affected by CO, demonstrating levels above 20% can result in the impairment of arrhythmia, premature ventricular contractions, task and neurophysiologic functions atrial fibrillation, heart block and ischemic in healthy subjects. Seizures and coma can be changes. The brain is the most sensitive target common in carboxyhemoglobin levels greater than site, manifesting neurologic symptoms. 40% and unconsciousness or death is likely above Effects of CO exposure vary with the concentra- 60%. Carboxyhemoglobin related hypoxic stress tion and duration, and range from rather subtle appears to be responsible for cardiac injuries, vascular and neurologic changes to unconscious- fatalities, and acute neurological abnormalities ness and death. Patients who die of CO poisoning found in approximately 15% of those who survive are characterized by diffuse petechia and hemor- CO poisoning. Other systemic complications rhages with edematous brains. Ischemic anoxia is which occur as a result of CO poisoning include: prominent in those patients who initially survive necrosis, renal failure, pancreatitis, acute CO poisoning and die within a few weeks. and hepatocellular injury (Mennear, 1993; Horner, Ambient CO exposure can cause pulmonary cell 2000). damage, as a direct result of CO uptake and not because of a CO to hemoglobin interaction. Table 2 lists examples of ambient CO concentrations, 6. Delayed neurological damage estimated carboxyhemoglobin levels that might result as steady-state exposure, and related human An insidious effect of CO poisoning is the health effects. Keep in mind that individuals may development of late neuropsychiatric damage, or experience different symptoms of CO toxicity even delayed neurological syndrome. Between 5 and under similar exposure conditions. Below carbox- 40% of CO exposed patients may manifest cogni- yhemoglobin levels of 10%, most subjects are tive difficulties, such as poor concentration, mem- asymptomatic. A carboxyhemoglobin concentra- ory loss and cognitive impairment within several tion of 2.5% has been proposed as the no-effect days to a month after exposure. Up to 40% of level. The proposed level is lower than the 3.5% patients develop memory impairment, with dete- S.T. Omaye / Toxicology 180 (2002) 139Á/150 145

Table 2 Ambient CO, carboxyhemoglobin and associated human health effects

Ambient CO COHb in blood (%) Human heath, symptoms and effects

% ppm

0.001 10 2 Asymptomatic 0.007 70 10 Exhaustion in healthy people, more angina in patients, headaches 0.012 120 20 Dizziness, nausea, dyspnea 0.022 220 30 Visual disturbances 0.035Á/0.052 350Á/520 40Á/50 Confusion, syncope, seizures and coma 0.080Á/0.195 1950 60Á/80 Cardiopulmonary dysfunction and death

Modified from; Varon et al., 1999; Raub et al., 2000; Horner, 2000. rioration of personality. It appears many cases CO for 1 h) caused more rapid onsets of exercised- may be consequences of missed diagnosis. This is induced anginal pain in male subjects with stable unfortunate because complete recovery may be angina (Kleinman et al., 1989). Others have found obtained when intervention by supplemental oxy- that 5.8% carboxyhemoglobin saturation resulted gen is initiated soon after diagnosis. Neuronal in increased frequency and complexity of post- death in the cortex, hippocampus, exercise ventricular arrhythmias, compared with and globus pallidus is all an effect with CO 3.9% carboxyhemoglobin saturation (Sheps et al., poisoning. Demyelination of the cerebral cortex 1990). Thus, several studies in humans strongly and a broken bloodÁ/brain barrier are common suggest that exposure to high concentrations of abnormalities found in patients of CO poisoning. CO may elevate risk of ischemic heart disease. As noted above, such effects are consistent with the production of systemic anoxia and impaired 6.1. Cardiovascular diseases myocardial tissue. In addition, tobacco smoke or smoke resulting from the environment of smokers, Workers exposed to automobile exhaust (50 could contribute to the CO load of individuals; ppm of CO) in tunnels were reported to have however, the significance of such contribution has 35% excess in ischemic heart disease death (Stern been debated (Mennear, 1993). et al., 1988). We have looked at the association between hospitalization for cardiovascular system illnesses and ambient levels of CO in the RenoÁ/ 7. Biochemical changes. Sparks area of Northern Nevada. The RenoÁ/ Sparks area is unique because of its high altitude Other mechanisms not related to tissue hypoxia and low concentration of dioxide. Accord- have been described as involved in the adverse ing to our statistical models, a consistent positive effects of CO poisoning, such as reoxygenation relationship exists between the ambient CO level injury (Zhang et al., 1992), products from the and different groups of xanthine /oxidase reaction, or nitric hospital admissions, although the male group oxide derived oxidants (Thom, 1992; Thom et al., and the /60 years old group tended to have the 1997). highest correlations of all groups studied (Yang et al., 1998; Chen et al., 2001). Our findings are consistent with those of other studies (Schwartz et 7.1. Mitochrondrial dysfunction al., 1995; Schwartz, 1997; Burnett et al., 1997a,b), supporting the role of ambient CO in hospital contained in complex III (succi- admissions for heart disease. Carboxyhemoglobin nate-coenzyme Q reductase) and complex IV level changes from 1.5 to 3% (exposure to 100 ppm () of the mitochondrial 146 S.T. Omaye / Toxicology 180 (2002) 139Á/150 respiratory chain are targets for CO because they carboxyhemoglobin is 5.3 h. Administration of contain heme groups. It has been reported that 100% oxygen at one atmosphere reduces the half cytochrome c oxidase activity returned to normal to 1.3 h, and with 100% oxygen at three level much more slowly than did carboxyhemoglo- atmospheres will reduce the half life to 0.4 h. bin levels following treatment. Thus, cytochrome c Adding may also be beneficial oxidase inhibition could be crucial for some of the because it reduces the half-life of carboxyhemo- symptoms ascribed to CO toxicity, such as delayed globin to 12 min in a patient hyperbaric neuronal injury. In rats, it has been demonstrated oxygen. This is due to the stimulation, by carbon that cerebral oxidative injury is not the direct dioxide, of alveolar ventilation and acidemia, effect of hypoxia, but rather due to ROS generated which increases the dissociation of carboxyhemo- in brain mitochondria (Zhang et al., 1992). Similar globin. results have been found in circulating lymphocytes from patients acutely intoxicated by CO (Miro et 8.2. Iron and copper al., 1999). Enhanced oxidative damage of lipid membranes related to inhibition of mitochondrial Both iron and copper-containing proteins are could play a key role in the pathophysiol- important targets for forming the CO ligand. ogy of CO toxicity. Obviously, dietary deficiencies of either element can have accentuating consequences in CO poi- 7.2. Interaction of CO and NO soning. Iron intakes are frequently inadequate in some population groups, noted aboveoverlap with As little as 22 nM of CO can elevate tissue nitric the high risk groups for CO poisoning. These oxide (+NO), which can occur when interstitial CO groups include: infants and young children, ado- partial is approximately 20 ppm with a lescents, females during childbearing years, and 7% carboxyhemoglobin level. The +NO level pregnant women. Other conditions associated with increase is not due to increased enzyme synthesis increased need for intake due to iron losses or but because competitive binding with CO for impaired iron absorption: hemorrhage prone, intracellular heme protein binding sites (Fig. 7). protein calorie , renal disease, de- CO has a stronger affinity than +NO for heme creased gastrointestinal transit time, steatorrhea, protein binding sites. Subsequently, increased intestinal parasites, achlorhydria and prolonged vascular +NO will promote oxidative stress, leak- use of alkaline-based , e.g. . The age of various mediators, and trigger phagocyte impact of iron deficiency on anemia is not really adherence/activation. evident until iron depletion is severe. However, there are significant health effects that can be attributed to iron deficiency without anemia. Iron deficiency in children can result in pallor, beha- 8. interactions vioral disturbances, lack of ability in cognitive tasks, some irreversible impairment of learning 8.1. Oxygen ability, and shorter attention span. In older people, iron deficiency without anemia, can lead Patients with CO poisoning respond to treat- to decreased work performance and . ment with 100% oxygen, both normal or hyper- Likely modes of action may be by either impairing barometric situations. The mean half-life of degradation of gamma-amino (GABA), an inhibitory in the brain, or inhibiting producing . Thus, it is easy to conclude that iron deficiency could further compromise an individual exposed to CO, with respect to oxygen carrying ability and Fig. 7. Displacement of nitric oxide by CO. various health indices that involve iron metabo- S.T. Omaye / Toxicology 180 (2002) 139Á/150 147 lism. Currently, there is little information available likely that antioxidant , such as vitamins about the benefit of iron supplementation as an CandEhave important roles as adjuvants in CO- adjunct in CO therapy, with the possible exception induced damage. of individuals with iron deficiency. In addition to CO effects, smoke is rich in ROS Various clinical symptoms are associated with and can induce the respiratory tract production of human copper deficiency, which are somewhat endogenous oxidants and ROS via the inflamma- similar to those described for iron. Recognized tory response. It is likely that smoke exposure can symptoms include hypochromic anemia, leukope- levy a heavy toll on the body’s natural antioxidant nia, hypopigmentation or depigmentation of defense systems, depleting tissue pools of critically and hair, impaired immune function and bone needed antioxidants. This has been demonstrated abnormalities. In addition, the risk of athero- in several nutrition surveys for smokers, showing sclerosis is higher with copper deficiency. In that this population suffers from low blood levels copper-deficient , is of antioxidants. In part, low antioxidant reserves found. Elevated blood pressure and plasma cho- reflect poor dietary habits and a consumption lack lesterol have been seen in some humans with low of fruits and vegetables. Several clinical trials have copper status. Therefore, CO poisoning super- explored the use of selected antioxidant supple- imposed on copper deficiency would further com- ments in preventing various adverse effects; how- promise subcellular energy production and elevate ever, the findings have been less than promising in the level of oxidative stress. support for the use of supplements. For example, results from the Physicians’ Health Study () 8.3. Antioxidants and the Beta-Carotene and Trial (CARET) indicated that supplements of E Oxidative stress plays an intimate role in the had little affect and supplements of b-carotene progression of CO-induced tissue damage, but increased the incidence of lung (Hennekens particularly during the ischemic and reperfusion et al., 1996; Omenn et al., 1996). Thus, use of phase of CO-induced injury. Also, oxidative stress antioxidants may be efficacious for treatment of induced by CO toxicity may play a significant role the adverse effects of CO; but caution is warranted in various chronic diseases, such as cardiovascular diseases. Evidence of high intakes of in the use of scientific approaches to designing associated with lower risk of heart disease has been such treatment, rather than using hit-or-miss or shown in studies involving large groups of men shot-gun approaches. and women. An increased risk of ischemic heart Ascorbic acid is the most important water- disease has been shown with low plasma concen- soluble, essential antioxidant present in human tration of antioxidants, primarily vitamin E, but to and blood. Relatively high concentrations a lesser extent with carotene, and of ascorbic acid are found extracellularly, and this . Antioxidant supplementation studies vitamin functions well as an antioxidant and have shown some promising results, such as scavenger of superoxide anion , singlet diminished risk of heart disease. Recovery of tissue oxygen, hydroxyl radical and in preventing lipid following ishcemic-reoxygenation injuries also ap- peroxidation (Elsayed et al., 2001). Ascorbic acid pear to benefit from the use of antioxidants. has been shown to protect DNA and other , both normal and hyperbaric from oxidative-induced damage. levels, are the accepted means for CO treatment. It As the major water-soluble antioxidant, ascorbic is well established that such treatments increase the acid serves as the first-line-of-defense against risk of further complications due to increased damaging byproducts of oxidative stress. Ample oxidative stress. Patients who are subject to evidence exists supporting the role of ascorbic acid oxygen therapy might benefit by the use of in regenerating the antioxidant properties of a- antioxidant supplements, i.e. prevention of side , the important lipid-soluble antioxi- effects due to increased oxidative stress. Thus, it is dant. Other important water-soluble antioxidants 148 S.T. Omaye / Toxicology 180 (2002) 139Á/150 include: , lipoic acid and other thiol (approximately the level of oxygen found in living compounds. tissues), the difference in effectiveness decreases by It is likely that a-tocopherol is the key lipid- 40%; that is, b-carotene has enhanced antioxidant soluble, oxidation chain breaker and quenching activity at lower oxygen tension. At even higher free radical compound. In addition to its antiox- oxygen tension (760 Torr or 100% oxygen), any idant role, a-tocopherol provides membrane sta- antioxidant activity of b-carotene appears to be bility. Other important lipid-soluble antioxidants offset by b-carotene acting as a pro-oxidant. include: b-carotene, , and uric acid. Recent studies verifying the pro-oxidant effect of b-carotene have also shown the oxidative modifi- 8.4. Potential interactions promoting prooxidant cation of protein, fatty acids, and DNA (Zhang et effects al., 2000, 2001a,b). Extrapolating such findings to in vivo situations, the potential harm versus Due to several unanticipated clinical findings benefits of b-carotene is alarming. b-Carotene testing the efficacy of antioxidants in modulating would be useful when oxygen was less available chronic disease, a number of recent studies have (hypoxia, such as might be induced by CO) found that antioxidants can exhibit adverse effects. compared with ambient situations. However, b- Vitamin E compounds can act as pro-oxidants, carotene would be contraindicated in situations of particularly the tocopheroxyl radical (Pokorny et high oxygen tension, such as , oxygen al., 1987; Thomas et al., 2000). When the concen- therapy, and in reperfusion/reoxygenation injury, tration of tocopheroxyl radical is high enough, it is which might occur in the latter stages of CO possible for a number of undesirable side reactions poisoning or in attempts to use oxygen interven- to occur, leading eventually to enhancing lipid tion. peroxidation. Under mild oxidation conditions, It has become more evident that extensive vitamin E can accelerate the lipid peroxidation of interactions between antioxidant compounds, low-density (LDLs) isolated from both synergistic and antagonistic, both antioxi- human blood (Bowry et al., 1992, 1993; Ingold et dant and pro-oxidant, occur in vivo. No longer al., 1993). Such situations where LDL oxidation is can we assume that the outcome of their total initiated by reactions with various attacking aqu- action is equal to the sum of each antioxidant eous radicals, vitamin E residing at or near the entity alone. For example, the intake of excessive surface of the lipid membranes of the amounts of one antioxidant compound in the particles, may form vitamin E radicals. Subse- presence of other oxidants may lead to more quently, the LDL particle it to propagate overall oxidation rather than some synergistic the radical chain by its reaction with polyunsatu- response. Thus, studies on a single antioxidant rated fatty acids (PUFA) within the particle, and may be misleading if likely interactions are not such vitamin E radicals are not able to escape and considered. If we are to consider the use of propagate the radical chain with PUFA within the antioxidant compounds as adjuvants to CO ther- particle, particularly, if another reductant (co- apy, then we must insure that we consider antioxidant), such as ascorbic acid, is not available ramifications of potential interactions between in the aqueous phase outside the LDL particle such compounds. (Thomas et al., 2000). The antioxidant/pro-oxidant activities of b-car- otene and are related to environmental 9. Conclusion conditions, such as the concentrations of oxygen, b-carotene, and the presence of other oxidants The effects of CO appear to be biphasic, a (Burton et al., 1984; Lieber et al., 1996; Zhang et at high concentration with some apparent al., 1998). At 150 Torr (composition of air), a- benefits at low doses. The role of CO toxicity and tocopherol is about 40- to 50-fold better than b- heme protein is well established and provides the carotene as an antioxidant. However, at 15 Torr basis for therapies. The metabolically S.T. Omaye / Toxicology 180 (2002) 139Á/150 149 beneficial effects of low dose CO involving inter- Cobb, N., Etzel, R., 1991. Unintentional carbon monoxide- actions with NO and are just related deaths in the United States, 1979Á/1988. J. Am. Med. Assoc. 266, 659Á/663. beginning to be appreciated, as is our under- Elsayed, N.M., Bendich, A., 2001. 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