Chem. Res. Toxicol. 1995,8, 111-116
111
Mechanism of the Manganese-Catalyzed Autoxidation of Dopamine Roger V. Lloyd Department of Chemistry, University of Memphis, Memphis, Tennessee 38152 Received June 27, 1994@
Manganese is an essential trace element for human metabolism, but at higher concentrations it is a potent neurotoxin that presents clinical symptoms similar to those of Parkinson’s disease. Since the toxicity of manganese may be related to its ability to accelerate the oxidation of catecholamines, we have examined the effect of aqueous Mn2+ on the formation and decay of the dopamine semiquinone radical ion. ESR spectroscopy was used to measure the kinetics of the disappearance of the semiquinone radical spectrum and the simultaneous appearance of the six-line spectrum of aqueous Mn2+ in Tris buffer. From the proposed mechanism for the autoxidation of dopamine to the quinone, the rate expression for semiquinone radical disappearance has the functional form -rate = k’[D(OH)21[Mn2+lat constant pH and molecular oxygen concentration, while the pH dependence is given by -log(rate) = log(constant) (2 x pH), in agreement with the experimental results. The autoxidation of dopamine is catalyzed by manganese through the formation of a highly reactive complex. The effect of manganese is due to the fact that it can participate in a redox cycle which involves intramolecular electron transfer between manganese and the dopamine ligand.
+
Introduction Manganese is an essential trace element for human metabolism, but a t higher concentrations it is a potent neurotoxin. It presents clinical symptoms remarkably similar to those of Parkinson’s disease (1-3),which is believed to be caused in part by a reduction of the level of dopamine in the brain stem (4). Manganese-induced Parkinsonism has been observed a t blood manganese concentrations of 3 pM (5). Similar therapies are used in the treatment of manganese toxicity and of Parkinson’s disease, such as administration of the dopamine precursor L-dopa (6). It has also been suggested that manganese neurotoxicity is related to the fact that 6-hydroxydopamine, a known neurotoxin, is a product of the manganesecatalyzed autoxidation of dopamine (7). Relative to its toxicity, a key property of manganese may thus be its ability to accelerate the oxidation of catecholamines (2, 8). Donaldson et al. (1)measured the effect of manganese and other divalent metal cations on the autoxidation of dopamine, D(OHI2, to an aminochrome presumably via the semiquinone radical intermediate, DOz*-, and dopaquinone, DQ (Scheme 1). They monitored spectrophotometrically the concentration of aminochrome, the first readily detectable and stable oxidation product, and found Mn2+to be by far the most efficient catalyst for its formation of all the ions studied. Aminochrome is obviously not the initial product of dopamine oxidation (81, but the effect of Mn2+on the rate of formation of the semiquinone radical intermediate was not studied. Grinstead (9)also observed that the rate of oxygen absorption in the metal-catalyzed oxidation of pyrocatecholwas more rapid with Mn2+than with other ions, and Mn2+is known to catalyze the oxidation of adrenaline (10). The presence of diamagnetic metal ions such as Zn2+, Cd2+,and Mg2+has almost the opposite effect. They have been used quite successfully to increase the kinetic @
Abstract published in Advance ACS Abstracts, November 15,1994.
stability of semiquinone radical ions for observation by electron spin resonance (ESR)spectroscopy (11-14). Zinc readily complexes with the radicals from catechols such as dopa or dopamine, and the ESR signal intensity is proportional to Zn2+ concentration, but equimolar or greater concentrations of metal ion to substrate are needed (11). This is consistent with the observations of Donaldson (1) that these ions did not catalyze the autoxidation of dopamine. Plancherel and Zelewsky (15) also noted that diamagnetic salts strongly increased the radical concentration when the metal ion reacted with a semiquinone radical that was formed by single electron transfer from ruthenium-bipyridyl. However, the effect of redox-active transition metals on radical stability has not been much explored. Iron was shown to oxidize the neurotoxin 6-hydroxydopamine to its semiquinone radical (161, and metal ions, possibly as metal-oxygen complexes, appear to be necessary for its autoxidation (17). In this report, we have examined the effect of catalytic levels of the Mn2+ion on the formation and decay of the dopamine semiquinone radical ion.
Experimental Section Dopamine (3,4-dihydroxyphenethylamine, hydrochloride salt) and Tris were from Sigma (St. Louis, MO), and MnClz was from Fisher (Pittsburgh, PA). The Tris buffer (100 mM, pH = 7.8, except for the experiments on pH dependence) was prepared with Milli-Q deionized water (Millipore Corp., Boston, MA) and stirred overnight with Chelex-100 resin (Bio-RadLaboratories, Richmond, CA) before use to remove adventitious trace heavy metals. For the pH-dependence experiments, the Tris buffer was adjusted with HC1 to the desired pH. The required volume of buffer solution, containing MnClz if desired, was presaturated with 0 2 gas, added to a weighed amount of dopamine, and quickly aspirated through Tygon capillary tubing into an ESR aqueous flat cell already placed in the cavity of a Varian E-4 or E-104 ESR spectrometer. The solution did not come into contact with any metal surfaces during this procedure. The spectrometer was interfaced to a computer for data acquisition, so that a series of scans could be obtained at fixed time intervals for later analysis. The signal was deliberately overmodulated to
0893-228x/95/2708-0111$09.00/0 0 1995 American Chemical Society
112 Chem. Res. Toxicol., Vol. 8, No. 1, 1995
Lloyd Scheme 1
H DQ
improve the s/N ratio, and all experiments were run at identical instrument settings. The time from mixing to the beginning of the first scan was 30 s, and the sample was scanned until the semiquinone radical spectrum was no longer detectable, which required from 5 to 40 min, depending on manganese concentration. For some experiments the spectrometer field sweep was set so that one line of the six-line ESR spectrum of aqueous Mn2+could be observed on the same scan as the semiquinone spectrum, and the intensities of both spectra could be simultaneously monitored. In other cases only the spectrum of the semiquinone radical was scanned. All experiments were run at ambient temperature (19 & 2 "C). Spectral simulations were obtained and signal intensities measured by means of a software package written by Duling (28).The intensity data were fitted to quadratic functions with a mathematical program (MATHCAD) and extrapolated to zero time, and it was assumed that intensities were proportional to concentration. Initial rates of reaction were defined as the slopes of plots of radical intensity versus time evaluated at zero time. The method of initial rates was used to evaluate the reaction because the known complexity of the reaction strongly suggests that after only a short interval further steps are occurring and other products are present. Also, the dissolved oxygen concentration is constant and reproducible at the s t a r t of each experiment.
Results Immediately after the buffer was added to the solid dopamine, the resulting solution began to turn brown, and the ESR spectrum of an organic free radical could be observed as soon as the scan was started. This spectrum decayed rapidly at rates depending on the concentration of added manganese, while the six-line spectrum of aqueous Mn2+in Tris buffer, which was not initially detected, appeared. The organic radical was identified as the dopamine semiquinone radical by comparison of the ESR parameters obtained from simulation of the spectrum with the literature values (19). Firstderivative ESR spectra obtained both with and without added Mn2+are shown in Figure 1, along with simulations based on the parameters listed in Table 1. Specific assignments are taken from the literature (19). In Figure 2, spectra taken at different times after mixing in experiments with and without added manganese are compared, and in Figure 3 the time dependencies of ESR intensities for runs with different Mn2+concentrations at constant dopamine concentration are shown. By the end of any experiment the solution was dark brown, almost black, in color, as noted previously (20).
Discussion The ESR spectra (Figure 1)and hyperfine splittings (Table 1)indicate that the Mn2+ion does not noticeably perturb the spin density distribution in the semiquinone radical, since results with and without manganese are essentially identical and not significantly different from the literature values for the dopamine semiquinone radical (in the protonated -NH form). This is somewhat unexpected, because previous observations of semiquinone radical spectra complexed with diamagneticmetal ions
A
4.0 Gauss
" V
Figure 1. (A)First-derivative ESR spectrum of the semiquinone radical prepared by the addition of 10 mM dopamine to oxygen-saturated 100 mM Tris buffer (pH = 7.8) at room
temperature; (B)simulation based on the parameters listed in Table 1;(C)the same system plus 100 pM Mn2+;(D) simulation based on the parameters listed in Table 1.The scan width is 20 G.
Table 1. Proton Hyperfine Splittings (G) protona 3 5 6 B (2)
10 mM dopamineb 0.42z t 0.01 3.49 0.96 2.87
10 mM dopamine 100 pM Mn2+ 0.42 3.50 0.94 2.88
+
lit. (ref 19)c 0.46 3.58 0.94 2.98
a See Scheme 1 above for numbering. bThe spectra were obtained in 100 mM Tris buffer, pH = 7.8. The spectrum was obtained by photolysis in deionized water at pH = 7.
suggested that some perturbation of the hyperfine splittings would have been observed, together with a small additional splitting from S6Mn(100% abundant, I = VZ), if the Mn2+was indeed complexed. However, our results suggest that there is an interaction between manganese and the semiquinone radical (i.e., complex formation), as shown by the effect of the Mn2+ion on initial organic radical intensity and on rate of decay (Figures 2 and 3). Unlike Mn2+,the diamagnetic ions used as spin stabilizers do not have a second accessible oxidation state, and there is only a small spin density on the metal ion. Our mechanism proposes the formation of an unstable complex, and a rapid single-electron transfer reaction involving the metal ion, rather than stabilization of the complex by the ion. The measured initial rate for decay of the radical from 10 mM dopamine with 100 mM Mn2+is approximately 50 times faster than for dopamine alone. In contrast, from an experiment using the spin stabilization technique with Zn2+to detect the semiquinone radical from
Chem. Res. Toxicol., Vol. 8,No. 1, 1995 113
Manganese-Catalyzed Autoxidation of Dopamine
2500
x .-c
1
' '
'bb 0
' O b b
b b
2000-
-.--9 g v)
C 0
0
1500-
C
m
1000:
e b
500-
0 b
*
Figure 2. First-derivative ESR spectra of the semiquinone radical with buffer containing 100 pM Mn2+,at different times (minutes) d e r mixing (left), and at the same times after mixing without manganese (right). All scans were taken with the same instrument settings and are plotted at the same vertical scale. The scan width is 100 G. The broad peak on the left of each spectrum is the Am1 = 4 2 line of aqueous Mn2+. 50
-
40
-
2400 7
2000
47
- 30v
9 m
; .-
..-C
20-
-
10-
0-
;J "
I
0
;
k
Ii
Yo
Time, minutes
1'2
1'4
16
.,
Figure 3. Effect of Mn2+concentration on semiquinone radical
decomposition for 10 mM dopamine in Tris buffer (pH 7.8): 0 pM Mn2+; 0 , 20 pM Mn2+;A, 60 pM Mn2+;V, 100 pM Mn2+.
dopa, the rate of termination of the Znzi-semiquinone complex was estimated to be 400 times slower than for the uncomplexed radical (11). Complexation with Zn2+ also slightly affected the observed hyperfine splittings, and satellite peaks from 67Znwere observed, indicating the formation of long-lived complexes. Likewise, the formation of a stable Cu2+-dopamine complex was suggested as the explanation for the fact that Cu2+was much less effective than Mn2+in catalyzing the decomposition of dopamine (I). Thus, in the manganese complex, unlike the spin-stabilized complexes, there is no measurable transfer of spin density from a stable ligand radical to the metal ion, and the ligand radical is actually destabilized, or made more reactive. Consistent with this, Sawyer and co-workers in a comparison of zinc and manganese(I1) complexes showed that oxidation of the manganese complexes occurred at less positive potentials than the zinc (22). In Figure 4 the intensities of the semiquinone radical ESR spectrum and the Mn2+ ESR spectrum from the same experimental runs are plotted versus time after mixing. The apparent induction period in the appearance of the latter spectrum is an artifact of measuring a weak,
20
40
60
80
100
Mn2* concentration, pM
Figure 5. Effect of initial dopamine and Mn2+ concentrations on initial rate in Tris buffer (pH 7.8). The initial rates are relative to the rate of disappearance of radical in the absence of Mn2+: 0, 5 mM dopamine; W, 10 mM dopamine; A, 20 mM dopamine. The 10 mM dopamine experiments were run in triplicate, and the error bars represent f l SD.
broad line in a noisy base line, and the final steady-state intensity of the Mn2+ spectrum was identical to that observed for Mn2+in the Tris buffer alone, showing that free Mn2+ ion was released during the reaction. Thus there was no net consumption of Mn2+ in the reaction, which is consistent with the description of manganese as a catalyst and with the proposed mechanism (see below). The anti-correlation of the intensities of the two signals is in agreement with observations that Mn2+ complexes with lower symmetry do not have detectable manganese ESR signals (21) and is another indication that there is a strong interaction between manganese and dopamine. The Mn2+concentration versus initial rate of dopamine disappearance a t constant dopamine concentrations is plotted in Figure 5 and ln([Mn2+])versus ln(-initial rate) in Figure 6. As required for pseudo-first-order-conditions, the slopes of the lines for the log-log plot are approximately 1.
Mechanism The observations discussed above are all consistent with the formation of a strong but highly reactive
114 Chem. Res. Toxicol., Vol. 8,No. 1, 1995
Lloyd 4.0 7
1
353.0
0 2
-
25-
07.0
7.2
Figure 6. Logarithm of Mn2+ concentration versus the loga-
rithm of the initial rates: 0, 5 mM dopamine; . , 10 mM dopamine, A, 20 mM dopamine. The slopes of the lines (fl SD) are 1.08 f 0.058, 1.10 f 0.055,and 1.37 f 0.17,respectively. complex between manganese and dopamine. The reactivity is directly related to the fact that Mn(I1) and Mn(II1) can participate in a redox cycle and is greatly influenced by the nature of the complexing ligand and the strength of the interaction (20, 21, 23, 24). The mechanism shown below has been proposed previously to explain the interaction of manganese and dopamine (4),but has not been supported by any direct observation of the semiquinone free radical intermediates. In the equations below, D(OH)2 = dopamine, 'DO2 = dopamine semiquinone anion radical, D02-Mn = dopamine-manganese complex, DQ = dopaquinone, K = equilibrium constant, and k = rate constant. Roman numerals indicate the manganese oxidation state. D(OH),
+ Mn2+2DO,-Mn(I1) + 2H+ k-1
k2
DO,-Mn(II)+ 0,- DO,-Mn(III)+
7.6
7.8
8.0
8.2
8.4
+ 0,-
Figure 7. Effect of pH on the initial rate of decomposition of the semiquinone radical in 100 mM Tris buffer containing 10 mM dopamine and 60 pM Mn2+.The rates are relative to the rate at pH = 7. The error bars represent fl SD for replicate determinations.
state intermediate and rearranging:
From reaction 1,
and
(1) Substituting into eq 6, the final expression is: (2) -
DO,-Mn(III)+
7.4
Buffer pH
in( [Mn"] )
+ 0,- -*D0,-Mn(III)2+ + 0;k3
+
(3)
d['DP2-Mn(III)2+l- k~l[D(OH),I[Mn2+1[0,1
dt
[H+12
+
k4['D02-Mn(III)2f] (11)
' D 0 2 - M n ( I I I ) 2 f ~ D Q Mn2+
(4)
+ 0, - DQ + 2H' + 0;-
Since the concentration of the radical complex is small, the second term of eq 11can be neglected, and the rate of decomposition of the radical is given by
(5)
,1 - d['D02-Mn(III)2+l R5 k ~ ~ [ D ( O H ) , l [ M n 2 ~ 1 [ 0(12) dt [H+12
Overall: D(OH),
(H20,)
The only organic species that is actually observed by ESR is the radical complex, *D02-Mn(III)2+, and its rate of disappearance (from eqs 3 and 4) is given by:
- dE'D02-Mn(III)2+l-
dt -k,[DO,-Mn(III)+I[O~l
+ k4['D02-Mn(III)2+l (6)
From eqs 2 and 3 the rate of formation of the dopaminemanganese(II1) complex is: d[DO2-Mn(III)+1 dt k,[DO,-Mn(II)1[0,1 - k,[DO,-Mn(III)+l[O,-l
(7)
Assuming that the D02-Mn(III)+complex is a steady-
For a constant concentration of molecular oxygen and at constant pH, the rate expression for radical disappearance has the functional form
-rate = k'[D(OH),I[Mn2fl
(13)
while the pH dependence of the rate has the form lodrate) = -log(constant)
+ (2 x pH)
(14)
The plot of pH versus initial rate (Figure 7) has a slope of 1.87 (1SD = 0.41), in good agreement with eq 14, as well as with the qualitative observations of Archibald and Tyree (20). In contrast to previous work (41, the slope indicates that two hydrogen ions are involved in the ratedetermining step rather than one, which is consistent
Manganese-Catalyzed Autoxidation of Dopamine
with eq 1. Similarly, the results plotted in Figures 5 and 6 show that the reaction is pseudo-first-order in the initial concentrations of both dopamine and Mn2+, as expected from eq 13. In our experiments the oxygen partial pressure was held constant, but Nachtman et al. (25)have shown that the rate of Mn-catalyzed oxidation was greatly increased in 95%0 2 relative to air, as would be expected from eq 12. Since it is involved in the reaction but does not appear in the overall equation, manganese acts as a catalyst, although the turnover number is not known. There is considerable literature support for the details of the mechanism shown above, in particular the presence of manganese complexes in a 11-111 redox cycle, although this has not always been explicitly recognized. The mechanism is very similar to that suggested for the metal-catalyzed oxidation of pyrocatechol, where Mn2+ gave the highest yield of quinone product of all the divalent transition-metal cations studied (9,26),and for the oxidation of the ligand (3,5-di-tert-butylcatechol) in a manganese-catechol complex (27). Sawyer and coworkers showed that a manganese-semiquinone complex reversibly binds molecular oxygen (28), and reactions analogous to eq 3 above between manganese complexes and superoxide are well established (29-32). Superoxide dismutase has been observed to prevent the manganesecatalyzed oxidation of dopamine, which would be consistent with the equations above (33). Intramolecular electron transfer has been proposed to occur during the oxidation of adrenaline in a copper-adrenaline complex (341, and there is crystallographic evidence for metalligand electron transfer in manganese-quinone complexes (35, 36). Finally, a Mn2+ complex has been observed to catalyze the oxidation of a catechol to the quinone (37). Graham ( 8 )has suggested that manganese toxicity is due in part to its ability to generate toxic semiquinones as well as quinones, but our mechanism indicates that the concentration of free semiquinone radicals would be lower in the presence of manganese, so that any toxic effects would instead be caused by further oxidation products and by hydrogen peroxide. Equations 1-4 are similar to the possible in vivo reactions of manganese presented by Graham (81,except that he did not explicitly consider complex formation. It has been proposed (20, 38) that the active agents in manganese toxicity are actually complexes of Mn3+, even when the manganese is added as Mn2+. This is entirely consistent with the present mechanism if the Mn3+is more strongly bound to dopamine than to buffer ligands. In summary, the autoxidation of dopamine is accelerated by manganese through the formation of a highly reactive complex. The catalytic effect of manganese is due to the fact that it can participate in a redox cycle which involves intramolecular electron transfer between manganese and the dopamine ligand.
References (1) Donaldson, J., LaBella, F. S., and Gesser, D. (1980)Enhanced autoxidation of dopamine as a possible basis of manganese neurotoxicity. Neurotoxicology 2,53-64. (2)Donaldson, J.,and LaBella, F. S. (1984)The effeds of manganese on the cholinergic receptor in vivo and in vitro may be mediated through modulation of free radicals. Neurotoxicology 5,105-112. (3)Donaldson, J., and Barbeau, A. (1985)Manganese neurotoxicity: Possible clues to the etiology of human brain disorders. In Metal Ions in Neurology and Psychiatry. (Gabay, S., Harris, J.,and Ho, B. T., Eds.) pp 259-285, Alan R. Liss, New York.
Chem. Res. Toxicol., Vol. 8, No. 1, 1995 116 (4)Florence, T. M., and Stauber, J. L. (1989)Manganese catalysis of dopamine oxidation. The Science ofthe Total Environment 78, 233-240. (5) Wang, J.-D., Huang, C.-C., HWang, Y.-H., Chiang, J. R., Lin, J.N., and Chen, J . 4 . (1989)Manganese induced Parkinsonism: an outbreak in a ferromanganese smelter. Br. J . Ind. Med. 46,856859. Mena, I., Court, J., Fuenzalida, S., Papavasiliou, P. S., and Cotzias, G. (1970)Modification of chronic manganese poisoning: Treatment with L-Dopa or 5-OH tryptophane. New Engl. J . Med. 282,5-10. Garner, C. D., and Nachtman, J. P. (1989)Manganese catalyzed auto-oxidation of dopamine to 6-hydroxydopamine in vitro. Chem.Biol. Interact. 69,345-351. Graham, D. G. (1984)Catecholamine toxicity: A proposal for the molecular pathogenesis of manganese neurotoxicity and Parkinson's disease. Neurotoxicology 5 , 83-96. Grinstead, R.R. (1964)Metal-catalyzed oxidation of 3,5-di-t-butyl pyrocatechol, and its significance in the mechanism of pyrocatechase action. Biochemistry 3,1308-1314. Harrison, W. H.(1963)Detection of intermediate oxidation states of adrenaline and noradrenaline by fluorescence spectrometric analysis. Arch. Biochem. Biophys. 101,116-130. Kalyanaraman, B.,and Sealy, R. C. (1982)Electron spin resonance-Spin stabilization in enzymatic systems: Detection of semiquinones produced during peroxidatic oxidation of catechols and catecholamines. Biochem. Biophys. Res. Commun. 106,11191125. Kalyanaraman, B., Felix, C. C., and. Sealy, R. C (1984)Electron spin resonance-Spin stabilization of semiquinones produced during oxidation of epinephrine and its analogs. J. Biol. Chem. 259,354-358. Kalyanaraman, B., Felix, C. C., and Sealy, R. C. (1984)Peroxidatic oxidation of catecholamines. J . Biol. Chem. 259,7584-7589. Kalyanaraman, B., Felix, C. C., and Sealy, R. C. (1985)Semiquinone anion radicals of catechol(amine)s, catechol estrogens, and their metal ion complexes. Environ. Health Perspect. 64,185198. Plancherel, D., and von Zelewsky, A. (1982)Photon-triggered complex formation: Radical complexes of o-benzosemiquinone, dopa, dopamine, and adrenaline formed by electron-transfer reaction from excited tris(2,2'-bipyridyl)ruthenium 11.Helv. Chim. Acta 65, 1929-1940. Floyd, R. A., and Wiseman, B. B. (1979)Spin-trapping free radicals in the auto-oxidation of 6-hydroxydopamine. Biochim. Biophys. Acta 586, 196-207. Gee, P., and Davison, A. J. (1984)6-Hydroxydopamine does not reduce molecular oxygen directly, but requires a coreductant. Arch. Biochem. Biophys. 231,164-168. Duling, D. (1994)Simulation of multiple spin-trap EPR spectra. J . Magn. Reson. 104,Ser. B, 105-110. Felix, C. C., and Sealy, R. C. (1981)Photolysis of melanin precursors: Formation of semiquinone radicals and their complexation with diamagnetic metal ions. Photochem. Photobiol. 34, 423-429. Archibald, F. S.,and Tyree, C. (1987)Manganese poisoning and the attack of trivalent manganese upon catecholamines. Arch. Biochem. Biophys. 256,638-650. Archibald, F. S.,and Fridovich, I. (1982)The scavenging of superoxide radical by manganous complexes: In vitro. Arch. Biochem. Biophys. 214,452-463. Richert, S. A., Tsang, P. K. S., and Sawyer, D. T. (1988)Ligandcentered oxidation of manganese(I1) complexes. Inorg. Chem. 27, 1814-1818. Halliwell, B.(1984)Manganese ions, oxidation reactions, and the superoxide radical. Neurotoxicology 5 , 113-118. Archibald, F. S.,and Fridovich, I. (1981)Manganese and defenses against oxygen toxicity in Lactobacillus plantarum. J. Bacteriol. 145,442-451. Nachtman, J. P., Delor, S., and Brennan, C. E. (1987)Manganese neurotoxicity: Effects of varying oxygen tension and EDTA on dopamine auto-oxidation. Neurotoxicology 8, 249-254. Tyson, C. A., and Martell, A. E. (1972)Kinetics and mechanism of the metal chelate catalyzed oxidation of pyrocatechols. J. Am. Chem. SOC.94,939-945. Chin, D.-H., Sawyer, D. T., Schaefer, W. P., and Simmons, C. J. (1983)Structural characterization of tris(3,5-di-tert-butylcatecholato)manganate(IV)and its redox reactions with superoxide ion. Inorg. Chem. 22, 752-758. Magers, K. D., Smith, C. D., and Sawyer, D. T. (1978)Reversible binding of dioxygen by tris(3,5-di-tert-butylcatecholato)manganese(II1) in dimethyl sulfoxide. J. Am. Chem. SOC.100,989-990. Stein, J., Fackler, J. P., Jr., McClune, G., Fee, J. A., and Chan, L. T. (1979)Superoxide and manganese(II1). Reactions of MnX-ray structure of EDTA and Mn-CyDTA complexes with 02-.
116 Chem. Res. Toxicol., Vol. 8, No. 1, 1995 KMnEDTA.2H20. Znorg. Chem. 18, 3511-3519. (30) Dam, D., Zarilla, K. A., and Fridovich, I. (1987) A mimic of superoxide dismutase activity based upon desferrioxamine B and manganesdm. Arch. Biochem. Biophys. 258,351-356. (31) Howie, J. E, and Sawyer, D. T. (1976) Manganese(11) and manganese(II1) 8-quinolinol complexes. Redox model for mitochondrial superoxide dismutase. J. Am. Chem. Soc. 98, 66986700. (32) Curnutte, J. T., Karnovsky, M. L., and Babior, B. M. (1976) Manganese-dependent NADPH oxidation by granulocyte particles. J. Clin. Invest. 67, 1059-1067. (33) Segura-Aguilar, J., and Lind, C. (1989) On the mechanism of the Mn3+-inducedneurotoxicity of dopamine: Prevention of quinonederived oxygen toxicity by DT diaphorase and superoxide dismutase. Chem.-Biol. Interact. 72, 390-324. (34) Walass, E., Walass, O., and Haavaldsen, S. (1963) Spectrophotometric and electron-spin resonance studies of complexes of catecholamines with Cu(I1) ions and the interaction of cerulo-
Lloyd
(35) (36) (37)
(38)
plasmin with catecholamines. Arch. Biochem. Biophys. 100,97109. Lynch, M. W., Hendrickson, D. N., Fitzgerald, B. J., and Pierpont, C. G. (1981) Ligand-inducedvalence tautomerism in manganesequinone complexes. J. Am. Chem. Soc. 103,3961-3963. Larsen, S. K., and Pierpont, C. G. (1988) Cobalt and manganese complexes of a Schiff base biquinone radical ligand. J.Am.Chem. SOC.110, 1827-1832. Gultneh, Y., Farooq, A., Karlin, K. D., Liu, S., and Zugieta, J. (1993) Structure and reactions of an eight-coordinate Mn(I1) complex: [Mn(TMPA)2](C104)2(TMPA = tris[(2-pyridyl)methyllamine). Inorg. Chim. Acta 211, 171-175. Donaldson, J. (1987) The physiopathologic significance of manganese in brain: Its relation to schizophrenia and neurodegenerative disorders. Neurotoxicology 8, 451-462.
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