Chem. Res. Toxicol. 2004, 17, 1145-1150
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9,10-Phenanthrenequinone, a Component of Diesel Exhaust Particles, Inhibits the Reduction of 4-Benzoylpyridine and All-trans-retinal and Mediates Superoxide Formation through Its Redox Cycling in Pig Heart Hideaki Shimada,† Michiko Oginuma,† Akira Hara,‡ and Yorishige Imamura*,§ Faculty of Education, Kumamoto University, 2-40-1, Kurokami, Kumamoto 860-8555, Japan, Laboratory of Biochemistry, Gifu Pharmaceutical University, 5-6-1, Mitahora-higashi, Gifu 502-8585, Japan, and Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Kumamoto 862-0973, Japan Received April 5, 2004
We have recently purified a tetrameric carbonyl reductase from the cytosolic fraction of pig heart (pig heart carbonyl reductase, PHCR), using 4-benzoylpyridine (4-BP) as the substrate. PHCR has the ability to catalyze efficiently the reduction of 9,10-phenanthrenequinone (PQ) contained in diesel exhaust particles (DEPs). Thus, the present study was attempted to characterize the inhibitory effect of PQ on the reduction of 4-BP and all-trans-retinal in pig heart cytosol. Of the DEP components examined, PQ was the most potent inhibitor for the reduction of 4-BP and all-trans-retinal in pig heart cytosol. PQ also inhibited competitively the 4-BP reduction. These results indicate that PQ inhibits the reduction of 4-BP and alltrans-retinal by acting PHCR present in pig heart cytosol. Furthermore, whether PQ induces the formation of superoxide anion radical was examined in pig heart cytosol. The absorbance of cytochrome c at 550 nm was increased with the time by adding PQ, and the increased absorbance was decreased in the presence of superoxide dismutase. A similar result was observed in the reaction system of recombinant PHCR. On the basis of these results, it is concluded that PQ not only inhibits the reduction of 4-BP and all-trans-retinal catalyzed by PHCR but also mediates superoxide formation through its redox cycling involved in PHCR. We propose the possibility that PQ disturbs the homeostasis of retinoid metabolism and induces oxidative stress in pig heart.
Introduction Diesel exhaust particles (DEPs) are one of the major air pollutants in urban areas. DEPs contain a variety of organic components, such as aliphatic hydrocarbons, polycyclic aromatic hydrocarbons, halogenated aromatic hydrocarbons, and quinones (1-3). Among these components, quinones are capable of catalyzing the generation of reactive oxygen species in biological systems, resulting in the induction of oxidative stress (4, 5). 9,10-Phenanthrenequinone (PQ) is produced from phenanthrene, which comprises 6% of the total organic extract of DEPs (1, 6), by photooxidation and is known as a relatively abundant quinone in DEPs (7). Furthermore, it has been reported that PQ is a good substrate for microsomal NADPH-cytochrome P450 reductase and that superoxide and hydroxy radicals generated during redox cycling of the quinone by this flavin enzyme mainly participate in the DEP-prompted oxidative stress (8). We have recently purified a tetrameric carbonyl reductase from the cytosolic fraction of pig heart (pig heart * To whom correspondence should be addressed. Fax: +81-96-3714151. E-mail:
[email protected]. † Faculty of Education, Kumamoto University. ‡ Laboratory of Biochemistry, Gifu Pharmaceutical University. § Graduate School of Pharmaceutical Sciences, Kumamoto University.
Figure 1. Stereoselective reduction of 4-BP to S(-)-PPOL by rPHCR.
carbonyl reductase, PHCR), using 4-benzoylpyridine (4BP) as the substrate (9). Furthermore, recombinant PHCR (rPHCR) is isolated from Escherichia coli cells expressing its cDNA, and the substrate specificities of the rPHCR are almost the same as those of native PHCR (10). The rPHCR has the ability to stereoselectively reduce 4-BP to S(-)-R-phenyl-4-pyrodylmethanol [S(-)PPOL], as shown in Figure 1 (10). Because PHCR efficiently reduces all-trans-retinal as the endogenous substrate (9), it probably plays a role in retinoid metabolism. PHCR can also catalyze the reduction of quinones (9). Unlike one-electron reduction of quinones catalyzed by NADPH-cytochrome P450 reductase, two-electron reduction of quinones catalyzed by carbonyl reductase has generally been thought to be a detoxification pathway since the resulting hydroquinones may serve as substrates for glucuronidation and sulfation reactions, which
10.1021/tx0499012 CCC: $27.50 © 2004 American Chemical Society Published on Web 07/28/2004
1146 Chem. Res. Toxicol., Vol. 17, No. 8, 2004
terminate redox cycling. However, Brown et al. (11) have shown that when these secondary reactions become limiting, the autoxidation of hydroquinones contributes to the generation of reactive oxygen species. In the heart, the presence of enzymes responsible for secondary reactions (conjugations) such as glucuronidation and sulfation is unknown. Thus, it is possible that the two-electron reduction of quinones catalyzed by carbonyl reductase involves redox cycling in the heart (12). In fact, menadione (vitamin K3, 2-methyl-1,4-naphthoquinone) and anthracyclines containing a quinone moiety have been shown to cause cardiac toxicity (13-15). Environmental quinones contained in DEPs are mainly absorbed from the lung and transported into the heart through the pulmonary vein. Because the heart shows a high expression level of PHCR as compared to the lung (9), it is important to examine the cardiac toxicity of environmental quinones induced by the enzyme. Interestingly, PQ is the best substrate of PHCR (9), suggesting that it competitively inhibits the reduction of 4-BP and all-trans-retinal in pig heart. Therefore, PQ may disturb the homeostasis of retinoid metabolism by inhibiting the reduction of all-trans-retinal to all-transretinol. The purpose of this study is to characterize the inhibitory effects of DEP components such as PQ on the reduction of 4-BP and all-trans-retinal in pig heart. Whether PQ mediates superoxide formation through its redox cycling is also examined in pig heart.
Materials and Methods Materials. The chemicals and proteins were obtained from the following sources. 4-BP, anthracene, β-naphthoflavone, cytochrome c, and superoxide dismutase (SOD, from bovine erythrocyte) were from Wako Pure Chemical Industries, Ltd. (Osaka, Japan); PQ, all-trans-retinal, and all-trans-retinol were from Sigma Chemical Co. (St. Louis, MO); and 1,2-naphthoquinone, 1,4-naphthoquinone, 9,10-anthraquinone, phenanthrene, and pyrene were from Aldrich Chemical Co., Inc. (Milwaukee, WI). NADPH, NADP+, glucose-6-phosphate, and glucose-6-phosphate dehydrogenase were purchased from Oriental Yeast Co. (Tokyo, Japan). S(-)- and R(+)-PPOL were synthesized from 4-BP (10). rPHCR was isolated from E. coli BL21(DE3)pLysS cells transfected with the plasmids harboring its cDNA as previously described (9). All other chemicals were of reagent grade. Preparation of Cytosolic Fraction. The pig hearts were supplied from a slaughterhouse and stored at -20 °C. The tissues were homogenized in 3 volumes of 10 mM sodium potassium phosphate buffer containing 1.15% KCl (pH 6.0). The homogenates were centrifuged at 105000g for 60 min to obtain the cytosolic fraction. Stereoselective Reduction of 4-BP. The enzyme reaction in the cytosolic fraction was conducted in an NADPH-generating system (50 µM NADP+, 1.25 mM glucose-6-phosphate, 50 mU glucose-6-phosphate dehydrogenase, and 1.25 mM MgCl2). The reaction mixture consisted of substrate (0.5 mM 4-BP), NADPHgenerating system, enzyme preparation (pig heart cytosol), and 100 mM sodium potassium phosphate buffer (pH 6.0) in a final volume of 0.5 mL. In the case of inhibition experiments, the organic components of DEPs including PQ dissolved in Me2SO were added at a concentration of 10 µM. The reaction mixture was incubated at 37 °C for 10 min and boiled for 2 min to stop the reaction. After centrifugation at 5000 rpm, the supernatant (20 µL) was subjected to HPLC for the determination of the reduction products, S(-)-PPOL and R(+)-PPOL, of 4-BP. HPLC was carried out using a Waters 600E HPLC apparatus (Japan Waters, Tokyo, Japan) equipped with a Daicel Chiralpak AD-RH column (Daicel, Tokyo, Japan) and a Waters 484 UV
Shimada et al.
Figure 2. HPLC separation of S(-)- and R(+)-PPOL generated from 4-BP. 4-BP (0.5 mM) was incubated with the reaction system of pig heart cytosol. Major and minor peaks correspond to S(-)- and R(+)-PPOL, respectively. monitor (254 nm). A mixture of 20 mM borate buffer (pH 9.0)acetonitrile (6:4, v/v) was used as a mobile phase at a flow rate of 0.5 mL/min. Kinetic Analysis. The inhibition of 4-BP reduction by PQ was kinetically analyzed using Lineweaver-Burk plots. The velocity (v) was expressed as µmol/min/mg protein. The protein concentrations were determined with bovine serum albumin as the standard by the method of Lowry et al. (16). Reduction of All-trans-retinal. The reaction mixture consisted of substrate (0.5 mM all-trans-retinal), NADPHgenerating system, enzyme preparation (pig heart cytosol), and 100 mM sodium potassium phosphate buffer (pH 7.4) in a final volume of 0.5 mL. In the case of the inhibition experiments, PQ dissolved in Me2SO was added at a concentration of 10 µM. The reaction mixture was incubated at 37 °C for 10 min and boiled for 2 min to stop the reaction. The preparation of the reaction mixture and the incubation were carried out in a dark room. After centrifugation at 5000 rpm, the supernatant (20 µL) was subjected to HPLC for the determination of the reduction product, all-trans-retinol, of all-trans-retinal. HPLC was carried out using a Tosoh DP-8020 HPLC apparatus (Tosoh, Tokyo, Japan) equipped with a Tosoh ODS-80Ts column and a Tosoh UV-8020 monitor (340 nm). A mixture of acetonitrile-1% ammonium acetate (4:1, v/v) was used as a mobile phase at flow rate of 1.0 mL/min. Determination of Superoxide Anion Radical. The superoxide anion radical was determined by the method of McCord and Fridovich (17) using cytochrome c. The reaction mixture, with a final volume of 1.0 mL, consisted of 100 mM sodium potassium phosphate buffer (pH 6.0), NADPH-generating system, 0.1 mM EDTA, 50 µM cytochrome c, and enzyme preparation (pig heart cytosol). In the case of the usage of rPHCR as the enzyme preparation, the NADPH-generating system was replaced by 0.5 mM NADPH. The reaction was started by the addition of 10 µM PQ. The reduction of ferricytochrome c (Fe3+) to ferrocytochrome c (Fe2+) in the enzyme reaction system was measured by recording the absorbance at 550 nm.
Results Stereoselective Reduction of 4-BP in Pig Heart Cytosol. The stereoselective reduction of 4-BP was examined in the cytosolic fraction from pig heart. Figure 2 shows HPLC separation of reduction products of 4-BP in pig heart cytosol. The reduction products appeared as a major peak corresponding to S(-)-PPOL. The enantiomeric excess (89.2% ee) of S(-)-PPOL produced in pig
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Table 1. Inhibitory Effects of Organic Components Contained in DEPs on the Stereoselective Reduction of 4-BP to S(-)-PPOL in Pig Heart Cytosola inhibition (%) components
10 µM
100 µM
9,10-PQ 1,2-naphthoquinone 1,4-naphthoquinone 9,10-anthraquinone phenanthrene anthracene β-naphthoflavone pyrene
86.7 ( 0.6 38.9 ( 5.6 17.0 ( 2.8 4.9 ( 2.0 5.5 ( 3.0 7.0 ( 3.3 8.5 ( 4.3 ND
# 89.8 ( 3.5 29.4 ( 5.5 9.3 ( 2.8 10.9 ( 3.7 12.9 ( 3.4 16.5 ( 3.9 10.9 ( 4.5
a Each value represents the mean ( SD of 3-5 experiments. 4-BP (0.5 mM) was used as the substrate. #, not determined. ND, not detectable.
Figure 4. Lineweaver-Burk plots for 4-BP reduction in the absence and in the presence of PQ. 4-BP at various concentrations was incubated with the reaction system of pig heart cytosol. O, in the absence of PQ; b, in the presence of PQ (1.0 µM). Each point represents the mean ( SD of at least two experiments.
Figure 3. Effects of PQ at various concentrations on the stereoselective reduction of 4-BP. 4-BP (0.5 mM) was incubated with the reaction system of pig heart cytosol. Each point represents the mean ( SD of three experiments.
heart cytosol was almost the same as that (87.2% ee) of S(-)-PPOL produced in the reaction system of rPHCR (10). Inhibitory Effects of Organic Components Contained in DEPs. Table 1 summarizes the inhibitory effects of organic components contained in DEPs on the stereoselective reduction of 4-BP to S(-)-PPOL in pig heart cytosol. Of these components, PQ was the most potent inhibitor for the stereoselective reduction of 4-BP. Significant inhibitions were also observed for 1,2- and 1,4-naphthoquinones. However, 9,10-anthraquinone, phenanthrene, anthracene, β-naphthoflavone, and pyrene were poor inhibitors. Furthermore, as shown in Figure 3, PQ exhibited concentration-dependent inhibition and the IC50 (concentration of 50% inhibition) value was 1.96 ( 0.27 µM. Kinetic Mechanism for the Inhibition of 4-BP Reduction by PQ. The inhibitory effect of PQ on the stereoselective reduction of 4-BP was kinetically examined in pig heart cytosol. As shown in Figure 4, PQ was found to competitively inhibit the 4-BP reduction. The Km and Vmax values for 4-BP reduction in the absence of PQ were 0.16 ( 0.04 mM and 4.22 ( 0.30 µmol/min/mg, respectively. On the other hand, the Km and Vmax values for 4-BP reduction in the presence of PQ were 0.44 ( 0.03 mM and 4.05 ( 0.39 µmol/min/mg, respectively. Inhibitory Effect of PQ on the Reduction of Alltrans-retinal. Figure 5A shows an HPLC chromatogram
of all-trans-retinol formed from all-trans-retinal in pig heart cytosol. PQ at a concentration of 10 µM inhibited the reduction of all-trans-retinal to all-trans-retinol, as shown in Figure 5B (inhibition percentage, 78.4 ( 1.8%). The highly efficient inhibitory effect was similar to that of PQ on the 4-BP reduction (86.7 ( 0.6%; see Table 1). On the other hand, phenanthrene, the parent compound of PQ, was a poor inhibitor for the all-trans-retinal reduction (6.7 ( 5.3%). Superoxide Formation through Redox Cycling of PQ. Quinones are known to generate superoxide anion radical through its redox cycling in several enzyme reaction systems (4, 5). Thus, whether PQ induces the formation of superoxide anion radical was examined in pig heart cytosol. As expected, the absorbance of cytochrome c at 550 nm was increased with the time by adding PQ (Figure 6). This is because ferricytochrome c is reduced to ferrocytochrome c. Furthermore, SOD was found to decrease the increased absorbance of cytochrome c at 550 nm (Figure 6). However, SOD had no effect on the stereoselective reduction of 4-BP in pig heart cytosol (data not shown), demonstrating that it has no ability to directly inhibit PHCR. These results indicate that PQ mediates the formation of superoxide anion radical through its redox cycling in pig heart. A similar result was observed in the reaction system of rPHCR (Figure 7). That is, the absorbance of cytochrome c at 550 nm was increased with the time by adding PQ, and the increased absorbance was decreased in the presence of SOD.
Discussion The exposure of humans and experimental animals to DEPs is associated with lung cancer, allergic inflammation, asthma, and cardiopulmonary diseases (18, 19). Thus, it is important to elucidate the detailed mechanism for the toxicity of components contained in DEPs. In the present study, we at first examined whether 4-BP is stereoselectively reduced to S(-)-PPOL in pig heart
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Figure 7. PQ-mediated reduction of cytochrome c in the reaction system of rPHCR. (a) PQ (10 µM) and (b) PQ (10 µM) + SOD (300 units).
Figure 5. HPLC chromatogram of all-trans-retinol generated from all-trans-retinal in the absence and in the presence of PQ. All-trans-retinal (0.5 mM) was incubated with the reaction system of pig heart cytosol. (A) In the absence of PQ; (B) in the presence of PQ (10 µM). Each value in parentheses represents the amount of all-trans-retinol generated from all-trans-retinal (mean ( SD, n ) 3, µmol/min/mg protein).
Figure 6. PQ-mediated reduction of cytochrome c in the reaction system of pig heart cytosol. (a) PQ (10 µM) and (b) PQ (10 µM) + SOD (300 units).
cytosol. As a result of HPLC, the major reduction product of 4-BP was S(-)-PPOL. The enantiomeric excess of S(-)-PPOL produced in pig heart cytosol was almost the same as that of S(-)-PPOL produced by using rPHCR as an enzyme preparation. These results suggest that the
stereoselective reduction of 4-BP is catalyzed by only PHCR present in pig heart cytosol. Because DEPs contain a variety of organic components (1-3), the inhibitory effects of these components on the stereoselective reduction of 4-BP in pig heart cytosol were compared. Of the components examined, PQ that is the best substrate of PHCR (9) was the most potent inhibitor for the stereoselective reduction of 4-BP in pig heart cytosol. In addition, PQ was confirmed to competitively inhibit the 4-BP reduction, indicating that this quinone competes with 4-BP for the substrate-binding site on PHCR. Recently, PQ has been reported to be a potent inhibitor of nitric oxide synthase and cyclooxygenase-2 (20, 21). However, so far, little is known about the inhibitory effect of PQ on carbonyl reductase. Our study is the first example demonstrating the inhibition of carbonyl reductase by PQ. PQ probably inhibits NADPHcytochrome P450 reductase and prostaglandin F synthase because of good substrates for these enzymes (8, 22). All-trans-retinoic acid is a metabolite of vitamin A (alltrans-retinol) that functions as an activating ligand for a family of nuclear retinoic acid receptors (23). All-transretinal is an intermediate in the production of all-transretinoic acid. Interestingly, PHCR has the ability to efficiently reduce all-trans-retinal to all-trans-retinol (9), suggesting that it plays a critical role in the homeostasis of retinoid metabolism in pig heart. The present study demonstrated that PQ strongly inhibits the reduction of all-trans-retinal to all-trans-retinol in pig heart cytosol and that the highly efficient inhibitory effect is similar to that of PQ on the 4-BP reduction. These results indicate that PQ causes the inhibition of the all-transretinal reduction by acting PHCR present in pig heart cytosol. We propose the possibility that PQ disturbs the homeostasis of retinoid metabolism in pig heart. Several studies have pointed out that carbonyl reductase mediates the redox cycling of various quinones (24, 25). For example, Jarabak (24) has shown that human placental carbonyl reductase catalyzes the redox cycling of menadione through a two-electron transfer mechanism. In the present study, PQ was found to mediate the formation of superoxide anion radical in pig heart cytosol. A similar result was observed in the reaction system of rPHCR. Cardiac DT-diaphorase is also known to be a
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responsible for the metabolic reaction of steroids, prostaglandins, and retinoids (9, 30-32). Recently, it has been reported that a regulated amount of all-trans-retinoic acid, the active form of retinoids, is required during critical early stages in cardiac cell differentiation (33, 34). Therefore, it is possible that exposure of the mother to PQ induces congenital abnormalities in the heart of the embryo, by strongly inhibiting the reduction of all-transretinal catalyzed by cardiac carbonyl reductase, i.e., by disturbing the homeostasis of retinoid metabolism during early embryonic development. Further studies are in progress to demonstrate the cardiotoxicity for the embryo of quinones contained in DEPs, especially o-quinones such as PQ and 1,2-naphthoquinone.
References Figure 8. Proposed model of superoxide formation during the redox cycling of PQ in pig heart.
cytosolic enzyme and to catalyze two-electron reduction of quinones (26, 27). However, a potent inhibitor of DTdiaphorase, dicoumarol at a concentration of 4 µM (27), had little effect on superoxide formation during the redox cycling of PQ in pig heart cytosol (data not shown). These observations suggest that PHCR is a main biocatalyst for the superoxide formation. SOD could not fully abolish the increased absorbance of cytochrome c at 550 nm. This may be because the semiquinone generated in this reaction system also reduces ferricytochrome c, as has been pointed out by Winterbourn (28). On the basis of these results, we conclude that PQ not only inhibits the reduction of 4-BP and all-trans-retinal catalyzed by PHCR but also mediates superoxide formation through its redox cycling involved in PHCR. A proposed model to fit evidence as described above is illustrated in Figure 8. PQ competes with 4-BP or alltrans-retinal for the substrate-binding site on PHCR and is subsequently reduced to the hydroquinone (PQH2) (eq 1):
PQ + NADPH + H+ f PQH2 + NADP+
(1)
Initially, a trace amount of superoxide anion radical (O2•-) oxidizes the hydroquinone, generating the semiquinone (PQ•-) and H2O2 (eq 2). The semiquinone then reduces O2, producing superoxide anion radical and the original PQ (eq 3). The superoxide anion radical in turn oxidizes the other hydroquinone:
PQH2 + O2•- f PQ•- + H2O2
(2)
PQ•- + O2 f PQ + O2•-
(3)
The hydroquinone also reacts with PQ to form the semiquinone in a so-called comproportionation reaction (eq 4) (29):
PQH2 + PQ f 2PQ•- + 2H+
(4)
The resulting semiquinone may produce the initial superoxide anion radical according to eq 3. However, a detailed mechanism including the identification of the hydroquinone remains to be elucidated. Carbonyl reductase is widely distributed in various tissues and physiologically functions as an enzyme
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