Article pubs.acs.org/JPCA
Effect of Blue Light on the Electronic and Structural Properties of Bilirubin Isomers: Insights into the Photoisomerization and Photooxidation Processes Lucas C. Cardoso, Ranylson M. L. Savedra, Mariana M. Silva, Giovana R. Ferreira, Rodrigo F. Bianchi, and Melissa F. Siqueira* Laboratório de Polímeros e Propriedades Eletrônicas de Materiais, Departamento de Física, Universidade Federal de Ouro Preto, Campus Morro do Cruzeiro, 35400-000 Ouro Preto, Minas Gerais, Brazil S Supporting Information *
ABSTRACT: The central process of neonatal phototherapy by employing blue light has been attributed to the configurational conversion of (4Z,15Z)-bilirubin to (4Z,15E). Indeed, photoisomerization is the early photochemical event during this procedure. However, in this paper, we show that the bilirubin solutions under continuous blue light exposure undergo a photooxidation process. To ascertain the role of this photodegradation in the phototherapy, we evaluated UV−visible absorption spectra obtained from bilirubin solutions in CHCl3, milli-Q water, and physiological saline, as well as FTIR spectroscopy for bilirubin in CHCl3. These analyses also showed that the first 2 h of phototherapy are the most relevant period. In addition, quantum molecular modeling using B3LYP/6-31G(d,p) and ZINDO/S-CIS was performed to evaluate the electronic and structural properties of four bilirubin isomers, showing that the (4Z,15E)-bilirubin isomer is the most polar configuration. Therefore, it can be more soluble in aqueous environments than the other configurations. This clarifies why this is the faster isomer excreted during the phototherapy.
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hydrogen bonding.12−14 Therefore, the surrounding water molecules cannot interact easily with this isomer as occurs with other bilirubin isomers.10−12 Phototherapy using blue light for the treatment of neonatal jaundice and related diseases triggers basically two main processes in the bilirubin molecules: configurational photoisomerization and structural changes.1,15 The first is related to reversible conformational changes in the bilirubin molecule, thereby converting the (4Z,15Z)-bilirubin into other isomers more hydrophilic and excretable. The latter is related to an irreversible structural rearrangement resulting in the lumirubin. Both come from the great contributions of McDonagh and Lightner.1,3,16−18 Nevertheless, photooxidation had been assumed to occur much more slowly and be less important
INTRODUCTION
Bilirubin is a neurotoxic breakdown product from the catabolism of heme cells. The accumulation of this yellow chromophore in the blood serum of newborn infants initiates the well-known neonatal jaundice.1−4 A continuous increase of bilirubin concentration in a newborn infant can lead to hyperbilirubinemia up to severe stages, such as chronic bilirubin encephalopathy, including kernicterus.2,4−6 Blue light phototherapy (focused on 460 nm) is the most widespread medical intervention, and is often the only treatment required for jaundice.7−9 The structure of bilirubin consists of two dipyrrinones, bridged by the group −CH2− that allows inner rotation into the molecule. Bonnet and co-workers elucidated the (4Z,15Z)configuration of bilirubin employing X-ray diffraction.10,11 The (4Z,15Z)-bilirubin isomer is naturally formed in the blood and is found at higher concentrations than the other configurations. The lipophilicity of (4Z,15Z)-bilirubin is due to intramolecular © XXXX American Chemical Society
Received: May 2, 2015 Revised: August 5, 2015
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DOI: 10.1021/acs.jpca.5b04225 J. Phys. Chem. A XXXX, XXX, XXX−XXX
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Figure 1. Schematic representation of photoisomerization and photooxidation processes of bilirubin.
used molecular quantum mechanical methods. For ease of reading, from now on we refer to the structures under study as ZZ, EZ, ZE, and EE, respectively. All the calculations were carried out using the Orca package, v 2.7.25 The calculations were performed employing density functional theory (DFT), by means of a full optimization of the structures using the hybrid functional B3LYP (DFT) associated with the 6-31G(d,p) basis set. This hybrid functional is the one most widely used in the literature to discuss the chemical properties of organic systems.26,27 The 6-31G(d,p) basis set associated with this functional has provided satisfactory results of electronic structure calculations for systems with the same molecular similarity to the bilirubin.27−30 In addition, frequency calculations were performed for all the isomers, to verify there was no imaginary value. Moreover, single electron excitations were undertaken within a CI space (15,15), using the ZINDO/S-CIS method to achieve electronic absorption spectra simulations.31−33 This semiempirical approach is computationally economical and provides results close to the experimental data to evaluate UV−visible absorption spectra.27,34−36 UV−visible Absorption and FTIR Spectroscopy. To assess the solvent effects on the process of bilirubin exposure under blue light, we evaluated three solutions, with a concentration of 200 mg/L: (i) CHCl3, (ii) deionized water, (iii) physiological saline. Due to the low solubility of bilirubin in aqueous solutions, we used the liquid phase for measurements. The bilirubin (C33H36N4O6, mixed isomers) was obtained from Sigma-Aldrich. The photodegradation experiments were performed by illuminating the bilirubin solutions with a commercial phototherapy system (Bilitron3006, 460 nm focus). These solutions were exposed to blue light for 4 h, maintaining the radiance at a controlled 40 W/cm2/nm. We used a UV−visible spectrometer Shimadzu 1650 series, which has an operating range from 190 to 1100 nm. The data were recorded every 5 min for the first 2 h of the radiation exposure process. Afterward, the data were recorded at
than the photoisomerization, although all configurations of bilirubin isomers are potent antioxidants.13,15,18,19 Accordingly, bilirubin is an oxygen-sensitive molecule. Thus, as the neonatal phototherapy procedure can occur at 4 to 6 h,1,20 the photooxidation process should be considered important for bilirubin elimination. Figure 1 shows a schematic representation of a proposal for the oxidation of bilirubin in a subsequent process after photoisomerization. The (4Z,15Z)-bilirubin isomer has been studied via spectroscopic characterizations, in solid, liquid, and gaseous states, using quantum mechanical calculations.19,21−24 Time dependent (TD-DFT) calculations carried out for the (4Z,15Z)-isomer have indicated two singlet transitions with the lowest energies.23 However, it has been reported that the second state may be an artifact of TD-DFT method. In addition, theoretical FTIR spectra has assigned the broad band at 3260 cm−1 as the NH lactamic stretching mode, and that at 1650 cm−1 has been attributed to the carboxylic CO stretching mode.21 In spite of information from electronic structure calculations about the structure of (4Z,15Z)-bilirubin, there has been a lack of discussion about the correlation between the isomer configuration changes during the photodegradation process. In this paper, we assess the profile of the FTIR and UV− visible spectra for in vitro bilirubin during exposure to blue radiation, and we discuss the photoisomerization and photooxidation processes. Concomitantly, the solvent effects (CHCl3, milli-Q, and physiological saline) are also evaluated. In addition, we treat the correlations between these results and the quantum molecular modeling calculations for the electronic properties of the 4Z,15Z; 4E,15Z; 4Z,15E; and 4E,15E bilirubin isomers.
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THEORETICAL AND EXPERIMENTAL DETAILS Molecular Quantum Mechanical Simulations. In order to investigate the electronic properties of four configurational isomers of bilirubin (4Z,15Z; 4E,15Z; 4Z,15E; and 4E,15E) we B
DOI: 10.1021/acs.jpca.5b04225 J. Phys. Chem. A XXXX, XXX, XXX−XXX
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The Journal of Physical Chemistry A 3 and 4 h. All samples were maintained at room temperature and under continuous stirring during the irradiation procedure. In addition, the solution of bilirubin in CHCl3 was evaluated through the use of FTIR spectroscopy. We used a Nicolet Magna 560 FTIR Spectrometer, with a nominal resolution of 2 cm−1 and wavelengths spanning the range from 4800 to 400 cm−1. The measurements were undertaken from drops of bilirubin in CHCl3 and ketone solutions, on a quartz plate, after the evaporation of the solvent. The spectra were recorded after 0, 60, 180, 240, and 360 min of the blue radiation procedure.
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RESULTS AND DISCUSSION Bilirubin in Chloroform Solution. The incidence of blue radiation on the skin of jaundiced patients during phototherapy
Figure 2. Normalized experimental UV−visible absorption spectra recorded for the bilirubin in chloroform solution under blue light exposure. The lines in gray are measurements obtained at 5 min intervals, until 2 h. The last data was obtained after 4 h of the procedure. The inset figure shows the decay of the rate I/I0 at a wavelength of 456 nm.
Figure 4. Normalized experimental UV−visible absorption spectra measured for bilirubin under blue light radiation exposure, over 4 h, in (a) milli-Q water and (b) physiological saline. These data were collected at intervals of 5 min in the first 2 h. The inset shows the ratio I/I0 as a function of time at 471 nm for milli-Q water and physiologic serum.
Table 1. Half-Life Calculated from the I/I0 as a Function of Time for Bilirubin in All Solutions under Blue Irradiation solution
τ1/2 (min)
CHCl 3 milli-Q physiological saline
61.0 25.4 37.0
(hypochromic effect) through the first 2 h for the bilirubin in chloroform solution under blue radiation exposure. According to the profile of these curves, the blue light has a minor effect on the solution after 3 h. These features show there is a chemical degradation of the sample due to the radiation, which makes it colorless. This arises from an oxidation process, since photoisomerization should only provoke shifts in the wavelength of the bands. In addition, we observed the noteworthy disappearance of the main band at 456 nm. The inset in Figure 2 exhibits a decay related to the rate I/I0 at a wavelength of 456 nm, where I is the molar absorptivity and I0 is this data at the beginning. In the Supporting Information, Table S1, we present the Boltzmann sigmoidal fitting. Moreover, in this section we also showed that
Figure 3. FTIR spectra measured for the bilirubin in chloroform solution, under blue light exposure at different times.
induces a series of chemical events, such as configurational changes in the bilirubin structure.1,3,37,38 Figure 2 shows a significant decrease in the maximum molar absorptivity C
DOI: 10.1021/acs.jpca.5b04225 J. Phys. Chem. A XXXX, XXX, XXX−XXX
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Figure 5. Molecular structural sketches for the four isomers of bilirubin under study: (a) EE, (b) EZ, (c) ZE, and (d) ZZ. The atoms are depicted by the following colors: blue for nitrogens, red for oxygens, white for hydrogens, and gray for carbons. We used the graphical interface package UCSF Chimera.41
Table 2. Frontier Molecular Orbital Energies and Band Gap, in eV configuration
HOMO−1 (eV)
HOMO (eV)
LUMO (eV)
LUMO+1 (eV)
band gap (eV)
EE EZ ZE ZZ
−5.14 −5.12 −5.09 −5.01
−4.92 −4.92 −4.92 −4.81
−2.05 −1.90 −2.09 −1.85
−1.77 −1.84 −1.77 −1.75
2.87 3.03 2.84 2.96
Figure 7. Magnitude of total dipole moments calculated for all bilirubin isomers under study, in debye.
volatilization of chloroform has no significant effect on the procedure used throughout the experiment time in Figure S1. Figure 3 shows the FTIR spectra of the bilirubin in chloroform solution under the blue radiation exposure procedure. After 1 h, there occurred a suppression of the band at about 750 and 1100 cm−1, assigned to N−H wagging and C−N stretching of the secondary amines, respectively. Moreover, we noticed a significant decrease of the bands related to the C−O axial stretching of the carboxylic acid, at 1275 cm−1, and the C−H axial stretching near 2900 cm−1. On the other hand, we observed an increase over time of the bands near 1700 cm−1 associated with CO stretching and a formation of a broad band around 3400 cm−1, which is characteristic of lactamic NH. These analyses corroborate our proposal on the important role of the photooxidation
Figure 6. Electronic absorption spectra (UV−visible) calculated for the bilirubin isomers under study, with no normalization: (a) EZ, (b) ZZ, (c) ZE, and (d) EE. The vertical lines indicate the transitions.
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exposure by means of experimental (CHCl3 and aqueous solutions) and theoretical analyses. Concerning the structural photoisomerization, our theoretical results showed that ZE is the most polar isomer of bilirubin and is relatively more soluble in water than the other isomers. Previous literature has reported that this isomer was detected after 15 min in blood samples during phototherapy.38 We observed that photooxidation already occurs within the first hour of exposure of bilirubin. This process was evinced by means of the progressive loss of solution color, verified from the decrease of intensity of the UV−visible absorption spectra. Moreover, to support this proposal, the FTIR spectra showed a concomitant increase of the CO band and the formation of a broad band related to the lactamic NH, during the blue light exposure in CHCl3. Thus, since phototherapy is a long-term process, both molecular events (photoisomerization and photooxidation) are able to occur and are responsible for the elimination of the unconjugated bilirubin excess in the blood during the phototherapy process.
process, as discussed above. As can be seen, some bands disappeared, and the CO band increased. Bilirubin in Aqueous Solutions. The effect of blue light on bilirubin in milli-Q water and physiological saline solutions was also traced by UV−visible absorption spectra for 4 h, Figure 4. In comparison to Figure 2, we observe a remarkable broadening of the characteristic bands for both aqueous solutions. Furthermore, a lowering of the molar absorption intensity (hypochromic effect) can already be seen in the first hour. The ratio I/I0 as a function of time at 471 nm, calculated for the bilirubin in milli-Q water, showed a similar decrease to that observed for the bilirubin in physiological saline solution, as can be seen in the inset of Figure 4b. However, the degradation process in physiological saline is slower than that in milli-Q water, suggesting that the use of salt retards the degradation. Table 1 shows the half-life (τ1/2) of the molar absorptivity decay calculated from a Boltzmann sigmoidal fit of the insets in Figures 2 and 4 for all bilirubin solutions studied. We clearly observed that bilirubin degradation occured more rapidly in aqueous solutions than in CHCl3. Bilirubin is a potent antioxidant;39,40 thus, it is oxygen-sensitive. Considering that the oxygen concentration in water is higher than in chloroform, this explains the fast decrease in the half-time of molar absorptivity of bilirubin in water. Moreover, the rate of degradation decreases in physiological saline, since oxygen solubility decreases slightly as salinity increases. Molecular Modeling of Bilirubin Isomers. Figure 5 shows the fully optimized structures of four bilirubin isomers, calculated using the B3LYP/6-31G(d,p) method. As can be seen, all configurational isomers of bilirubin are nonplanar, as expected. This is due to the sp3 carbon from −CH2− bridging the two dipyrrinone, and the intramolecular interactions. In general, the maximum wavelength we found for the main band of the isomers is at about 443 nm, except for the ZE isomer, which showed a redshift to 466 nm. Accordingly, the ZE isomer has the lower band gap energy, as shown in Table 2. We consider these results satisfactory when compared to the experimental wavelengths. All theoretical UV−visible absorption spectra (Figure 6) showed that the higher intensity band is from the π → π* transitions, which make the majority of the contribution from the HOMO → LUMO frontier molecular orbitals. We also observed a second band due to π → π* transitions for the EE, ZE, and EZ isomers. They are related to the contribution from HOMO−1 → LUMO+1 for the EE and ZE, while that for the EZ is from HOMO−1 → LUMO. Figure 7 shows the total dipole moment results. As can be seen, the ZE isomer has the highest polarity, followed by EE, ZZ, and EZ. Hence, the ZE is more soluble in aqueous solutions. Thus, it can be excreted more during the early stages of phototherapy.38 In comparison to Figure 6, we can notice a direct relationship between the maximum wavelength in the UV−visible spectra and the molecular dipole moments. These results lend support to our proposition that the more polar the isomer of bilirubin is, the higher the absorption wavelengths it exhibits. This indicates that the isomer with the higher polarity needs less energy to be electronically excited (Table 2).
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpca.5b04225. Boltzmann sigmoidal function, Boltzmann sigmoidal parameters (Table S1), UV−visible absorption spectra measured for a sample of bilirubin in chloroform without radiation exposure (Figure S1) (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors thank the Brazilian funding agencies CNPq, FAPEMIG, and CAPES, as well as the National Institute of Science and Technology on Organic Electronics (INEO/ INCT) for financial support and fellowships. In addition, we are also grateful to the group of polymers “Prof. Bernhard Gross” for computational support and the group of solid spectroscopy of the Physics Institute of São Carlos at the University of São Paulo for providing the FTIR for our measurements.
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REFERENCES
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CONCLUSIONS In this paper, we have discussed the photoisomerization and photooxidation processes in bilirubin under blue radiation E
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