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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS
1The Netherlands Cancer Institute, Division of Experimental Therapy, Amsterdam; 2Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, Groningen; and 3Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands
Submitted 28 June 2006 ; accepted in final form 14 February 2007
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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ATP binding cassette transporter; knockout mice; protoporphyria
Bcrp1–/– mice also display a novel type of porphyria (7). Porphyrias are metabolic disorders characterized by increased intracellular levels of porphyrins, the precursors of heme, and they are frequently associated with skin photosensitivity in patients (4). The Bcrp1 deficiency-related porphyria is unique as it is not caused by a defect in one of the enzymes of the heme biosynthetic pathway, in contrast to previously identified genetic porphyrias. Erythropoietic protoporphyria (EPP), for instance, is caused by a deficiency in ferrochelatase, the enzyme that mediates the conversion of protoporphyrin IX (PPIX) into heme (23). Transport by BCRP of some porphyrins may also impact cancer treatment using photodynamic therapy. Photodynamic therapy involves the administration of a photosensitizer, which selectively accumulates into and kills tumor cells after exposure to light (6). A variety of natural and synthetic porphyrins are currently used as photosensitizers, several of which have been demonstrated to be transported by BCRP (8, 20).
Although structural similarity with the porphyrin pheophorbide A, an excellent Bcrp1 substrate, and the transport of several other porphyrins by BCRP suggests that PPIX (or perhaps a PPIX derivative) might be transported by Bcrp1, the exact mechanism behind the protoporphyria caused by Bcrp1 deficiency is still unknown. Recently, the significance of BCRP for porphyrin homeostasis has been further substantiated by Krishnamurthy et al. (11), who demonstrated that under hypoxic conditions, cells can use BCRP to reduce heme or porphyrin accumulation, which can be detrimental for cells. Zhou et al. (27) further showed that erythroid cells overexpressing BCRP have significantly lower intracellular levels of PPIX. Together, these findings point toward a role for BCRP in the regulation of porphyrin homeostasis, possibly via transport of PPIX or of another porphyrin intermediate in the heme biosynthesis.
In the present study, we have identified the harderian gland as a novel expression site of Bcrp1. The harderian gland is a large intraorbital exocrine gland, located directly behind the eye. In rodents the harderian gland is especially well developed and characterized by the production and secretion of large amounts of porphyrins, the functional significance of which is unknown (17). Because of its pronounced role in porphyrin secretion, it offered us a useful tool to further study the mechanism of Bcrp1-dependent protoporphyria and transport of porphyrins in vivo. Complementing this, we also studied porphyrin accumulation and excretion by the liver.
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MATERIALS AND METHODS |
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Western blot analysis. Crude membrane fractions from tissues were prepared as described by Jonker et al. (7). Western blot analysis was performed as described using mAb BXP-53 (1:400) (11). mAb binding was detected using peroxidase-conjugated rabbit anti-rat IgG (1:1,000; DAKO).
Histological analysis and immunohistochemistry. Tissues were fixed in 4% phosphate-buffered formalin, embedded in paraffin, sectioned at 4 µm, and stained with hematoxylin and eosin according to standard procedures. For immunohistochemistry, tissues were deparaffinized in xylene and rehydrated. Endogenous peroxidase activity was blocked by using 3% (vol/vol) H2O2 in methanol for 10 min. Before being stained, paraffin sections were pretreated by heat-induced epitope retrieval. Slides were incubated with 5% normal goat serum/PBS for 30 min, and subsequently, sections were incubated overnight with a 1:400 dilution of BXP-53 at 4°C. mAb immunoreactivity was detected with the streptavidin-biotin immunoperoxidase method by using biotinylated goat anti-rat IgG (DAKO; 1:100) as secondary antibody, and diaminobenzidine substrate for visualization. After counterstaining with hematoxylin, the slides were mounted. For negative control, the primary mAb was omitted.
Biliary excretion experiments. Gallbladder cannulation experiments were performed as described previously (9) with minor adjustments. For anesthesia, a combination of ketamine (100 mg/kg) and xylazine (6.7 mg/kg) was injected intraperitoneally in a volume of 2.33 µl/g body wt. Gallbladder cannulation: after opening of the abdominal cavity and distal ligation of the common bile duct, a polyethylene catheter (Portex, Hythe, UK), with an inner diameter of 0.28 mm, was inserted into the incised gallbladder. The catheter was fixed to the gallbladder with an additional ligation. Bile was collected for 30 min (baseline fraction), followed by another 120 min (fractions of 30 min) after intravenous injection of 5 mg/kg PPIX (in DMSO) into the penile vein. At the end of the experiment, blood was collected by cardiac puncture.
PPIX determination.
Total levels of PPIX and its hydrophilic precursors were determined by HPLC analysis as described by Beukeveld et al. (1). Unconjugated PPIX and its glycoconjugates (protoporphyrin-1-O-acyl-
-xyloside and protoporphyrin-1-O-acyl -glucoside) were determined by HPLC analysis coupled with tandem mass spectrometry modified from a method described by Lim et al. (13). An HPLC system (model 1100; Agilent Technologies, Palo Alto, CA) was used, consisting of a binary pump, auto sampler, degasser, and column oven. Chromatographic separations of the analytes were carried out on a Phenomenex Luna C18 column, 250 x 4.6 mm ID, 5 µm (Phenomenex, Torrance, CA). From time 0 to 25 min, a mixture of 60% eluent A (20 mM ammonium acetate in water) and 40% eluent B (100% acetonitrile) was pumped through the column with a flow of 1 ml/min. Eluent B was raised to 90% from 25 to 30 min and maintained for 10 min. The column was reconditioned with 40% eluent B from 40.1 to 60 min. The respective retention times for protoporphyrin IX, protoporphyrin-1-O-acyl--xyloside, and protoporphyrin-1-O-acyl--glucoside were 
32.8, 34.0, and 32.2 min, respectively. The eluent was split 1:4 before entering an API2000 triple quadrupole MS equipped with a turbo ion spray source (Sciex, Thornhill, ON, Canada). The ion spray voltage was set at 4,500 V, and the source temperature was 300°C.
Sample preparation.
Harderian glands from 10 males were pooled and homogenized in 300 µl DMSO:acetonitrile (1:3, vol/vol). Livers were homogenized in DMSO:acetonitrile (1:3, vol/vol; 4 ml/g). Homogenates were centrifuged (5 min, 1,500 rpm, 4°C), and supernatants were diluted 4:6, vol/vol (sample extract: eluent A) before HPLC analysis. Mouse tears were collected by stimulation with the secretagogue carbamylcholine (10 µM) as described previously (5). Bile and tear samples were diluted 1:4, vol/vol (sample extract: eluent A) before HPLC analyis. Samples were diluted 2:3, vol/vol (sample extract: eluent A) before injection (10 µl). Three positive ion MRM channels were monitored at unit resolution corresponding to protoporphyrin IX (m/z 563 to 445), protoporphyrin-1-O-acyl--xyloside (m/z 695 to 563), and protoporphyrin-1-O-acyl--glucoside (m/z 725 to 563). The resulting MRM chromatograms were used for the quantification using Analyst software version 1.2 (Sciex). Total run time was 60 min.
Fluorescence microscopy.
For detection of porphyrin fluorescence, harderian glands were embedded in optimum cutting temperature compound (Tissue-Tek; Sakura Finetek Europe, Zoeterwoude, The Netherlands), sectioned at 4 µm, and examined microscopically. Fluorescence microscopy was performed with a Zeiss Axiovert 100 M microscope. Fluorescence was detected by measuring emission 
above 615 nm after excitation at 395–440 nm with an argon laser. Digital images were acquired with a Photometrics (Tucson, AZ) system consisting of a charge-coupled device camera (model CH250), an electronic unit (model CE 200A), and a controller board (model NU 200).
In vitro accumulation assay. Exponentially growing Madin-Darby canine kidney II cells and its derivatives overexpressing mouse Bcrp1 and human BCRP (8, 16) were incubated for 1 h at 37°C in DMEM medium with 10% FCS in the presence of pheophorbide A (10 µM) or harderian gland extract from Bcrp1–/– mice. Cells were trypsinized, washed, and suspended in Hanks' solution with 1% FCS. Light exposure was minimized, and after trypsinization all procedures were done at 4°C. Relative cellular accumulation was determined by flow cytometry with the use of FACScan (Becton Dickinson) with excitation at 488 nm and emission detection at 650 nm.
Statistical analysis. All values are given as means ± SD. The two-tailed unpaired Student's t-test was used to assess the significance of difference between two sets of data. Differences were considered to be statistically significant when P < 0.05.
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RESULTS |
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-xyloside ("penta") and protoporphyrin-1-O-acyl--glucoside ("hexa") (Fig. 4A) (13). Whether these PPIX-glycoconjugates are also present in other (porphyrinogenic) organs, such as the liver, is not known.
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-xyloside, but no unconjugated PPIX, was detected in mouse tears in both wild-type and Bcrp1–/– mice, suggesting that PPIX is mainly (if not only) excreted by the harderian gland as a conjugate (Fig. 5A). The level of protoporphyrin-1-O-acyl--xyloside in tears, however, was not significantly different between wild-type and Bcrp1–/– mice, but this may be due to the extreme accumulation of PPIX-conjugates in the harderian gland of Bcrp1–/– mice (Fig. 5A), likely resulting in a passive, Bcrp1-independent release of these conjugates from the harderian gland.
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-xyloside accumulated in the liver of Bcrp1–/– mice, whereas at the same time, levels of unconjugated PPIX were about twofold lower (Fig. 5C). Bile contained mainly unconjugated PPIX, which was about twofold higher in Bcrp1–/– mice (Fig. 5D). The fact that mainly unconjugated PPIX was detected in bile can be explained by a rapid deconjugation in bile. To test whether this was the case, we analyzed the rate of PPIX deconjugation in bile. Harderian gland extract from Bcrp1–/– male mice (containing high levels of primarily conjugated PPIX) was spiked into bile of wild-type male mice (containing very low levels of conjugated PPIX), and levels of PPIX and its conjugates were determined over a period of 30 min. Whereas PPIX was relatively stable, both PPIX conjugates were rapidly deconjugated (Fig. 4, B–D). In vitro transport of PPIX conjugates by Bcrp1/BCRP. To determine whether PPIX conjugates are directly transported by Bcrp1/BCRP, we measured their cellular accumulation by flow cytometry (Fig. 6, A and B). We used the canine epithelial kidney line Madin-Darby canine kidney II and its derivatives M-Bcrp1 and M-BCRP that overexpress Bcrp1 and BCRP, respectively, by retroviral transduction (8, 16). Because PPIX-conjugates are not commercially available, we used freshly prepared harderian gland extracts from Bcrp1–/– mice, which primarily contain conjugated PPIX (Fig. 5A). The relative accumulation of these compounds, as assessed by cellular porphyrin fluorescence, was dramatically reduced, nearly to the same extent as pheophorbide A, by both Bcrp1 and BRCP, indicating that they are efficiently transported by both murine Bcrp1 and human BCRP (Fig. 6, A and B).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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In contrast to the previously identified genetic porphyrias, Bcrp1-dependent protoporphyria is not caused by a defect in one of the enzymes of the heme biosynthetic pathway. Although relatively mild compared with EPP, and, in itself, not sufficient to cause phototoxicity, Bcrp1-dependent protoporphyria may increase phototoxicity caused by the dietary porphyrin pheophorbide A (7, 25). In this way, low or absent BCRP activity might also exacerbate the consequences of other genetic or drug-induced protoporphyrias and may explain some of the highly variable penetrance seen in these syndromes (23).
The regulation of intracellular levels of heme is thought to be tightly controlled through its synthesis and conversion via the enzymes 
-aminolevulinic acid (Ala)-synthase and hemeoxygenase, respectively (23). Little is known, however, about the mechanisms by which porphyrins are excreted by cells and how they are eliminated from the body. In addition to BCRP, two other porphyrin transporters have been recently identified (10, 19). First, FLVCR, a member of the major facilitator superfamily of transport proteins has been demonstrated to transport heme in humans. FLVCR is uniquely present at the CFU-E stage of erythrocyte differentiation and is proposed to be required for developing erythroid cells to protect them from heme toxicity (19). Second, ABCB6, a member of the ATP-binding cassette family, was identified as a mitochondrial porphyrin transporter (10).
In this study, we identified the mouse harderian gland as a novel expression site of Bcrp1. The harderian gland is an enigmatic and poorly understood orbital gland, which is present in most terrestrial vertebrates but only rudimentary in primates (17). In rodents the harderian gland is especially well developed and characterized by the production and secretion of large amounts of porphyrins. This high porphyrin production is a unique feature of the harderian gland and is attributed to a relatively high expression of Ala-synthase and relatively low expression of ferrochelatase (14). The mechanism and function of porphyrin secretion by the harderian gland are not well understood. The intraluminal pigmented masses, which are abundant in the harderian gland ducts of female rodents (Fig. 2A), have been shown to consist of complexes of porphyrins and lipids, as well as proteins. Furthermore, porphyrins are mainly localized in the cytoplasm of the tubulo-alveolar cells of the harderian gland, but not in the nucleus or in lipid droplets, suggesting that lipid-porphyrin complexes are probably formed in the glandular lumina and not within the glandular cells (15).
In this study, we have demonstrated that there is a massive accumulation of porphyrins in the harderian gland of Bcrp1–/– mice and that this is mostly due to the accumulation of protoporphyrin-1-O-acyl--xyloside and to a lesser extent of protoporphyrin-1-O-acyl--glucoside. A similar, although quantitatively much lower, accumulation of protoporphyrin-1-O-acyl--xyloside was observed in the livers of Bcrp1–/– mice. This is the first time that PPIX conjugates have been identified in the liver, and this finding suggests that the mechanism of excretion in the liver and harderian gland might be similar. It should be noted, however, that unlike the PPIX conjugates, levels of unconjugated PPIX were decreased both in the harderian gland and liver of Bcrp1–/– mice (Fig. 5, A and C). The exact reason for this is unclear, but it is possible that this is due to feedback regulation of PPIX synthesis or via an increased rate of its conjugation.
To gain more insight into the role of Bcrp1 in the excretion of these compounds, we determined their levels in tears and bile. We showed that mouse tears only contained the conjugate protoporphyrin-1-O-acyl--xyloside indicating that PPIX is mainly (if not only) excreted by the harderian gland as a conjugate. The observation that the level of protoporphyrin-1-O-acyl--xyloside was not significantly different between wild-type and Bcrp1–/– mice might be explained by the fact that there is an extreme accumulation of PPIX conjugates in the harderian gland of Bcrp1–/– mice, likely resulting in a passive, Bcrp1-independent release of these conjugates from the harderian gland. In contrast to tears, mainly unconjugated PPIX was detected in bile of both wild-type and Bcrp1–/– mice, even after high-dose intravenous administration. Interpretation of these data, however, is complicated by the high rate of deconjugation observed in bile (Fig. 4, B–D). It thus remains possible that Bcrp1 can also directly transport unconjugated PPIX, albeit with a much lower affinity than the PPIX glycoconjugates. This would also be consistent with the study by Zhou et al. (27) that suggested direct transport of PPIX by Bcrp1, but which was not designed for the detection of PPIX conjugates. Finally, our cellular accumulation experiments in cells overexpressing Bcrp1/BCRP support direct transport of PPIX conjugates by BCRP.
What might be the physiological function of transport of PPIX and its conjugates by BCRP? Since the function of the harderian gland itself is not well understood, this remains speculative. One possibility is that BCRP provides a mechanism to reduce porphyrin toxicity locally. Despite its exposure to high levels of porphyrin-derived reactive oxygen species, the harderian gland appears to be relatively resistant to oxidative stress. Recently, it has been suggested that the harderian gland might cope with this cellular damage by means of constant tissue renewal via autophagic and invasive processes (23). In addition, conjugation of PPIX and/or exretion by BCRP might provide additional levels of protection. In this way, BCRP might serve as an overflow system, which allows cells to rid themselves of excess PPIX via high-affinity transport of its conjugates, thereby preventing or reducing its cytotoxicity under excess conditions (e.g., harderian gland, pathological liver), but without spillage under physiological conditions when PPIX is needed (healthy liver). Alternatively, excretion of PPIX-conjugates from the harderian gland by BCRP could have yet unknown exocrine or endocrine functions (17).
Further insight into the role of BCRP in the transport and elimination of porphyrins could ultimately lead to improved treatment or prevention of porphyrin-related disorders. A large number of widely occurring polymorphic variants of BCRP have been detected in humans, some of which reduce or even abolish porphyrin transport (3, 21). The extent, however, to which reduced BCRP activity as a consequence of these mutations, or through (pharmacological) inhibition or downregulation affects porphyrin transport and elimination, has yet to be determined.
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ACKNOWLEDGMENTS |
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Present address for J. W. Jonker: The Salk Institute for Biological Studies, Howard Hughes Medical Institute, Gene Expression Laboratory, 10010 N. Torrey Pines Rd., La Jolla, CA 92037 (e-mail: hjonker{at}salk.edu).
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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