ToxSci Advance Access originally published online on March 6, 2007
Toxicological Sciences 2007 97(2):533-538; doi:10.1093/toxsci/kfm041
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Humanization of Excretory Pathway in Chimeric Mice with Humanized Liver
* Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Kakuma-machi, Kanazawa 920-1192, Japan
PhoenixBio Co. Ltd, Hiroshima, Japan
GenoMembrane Co. Ltd, Yokohama, Japan
Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co. Ltd, Tokyo, Japan
¶ Hiroshima Prefectural Institute of Industrial Science and Technology, Cooperative Link of Unique Science and Technology for Economy Revitalization, Hiroshima, Japan
|| Graduate School of Science, Hiroshima University, Hiroshima, Japan
1 To whom correspondence should be addressed. Fax: +81-76-234-4407. E-mail: tyokoi{at}kenroku.kanazawa-u.ac.jp.
Received February 3, 2007; accepted February 26, 2007
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The liver of a chimeric urokinase-type plasminogen activator (uPA)+/+/severe combined immunodeficient (SCID) mouse line recently established in Japan could be replaced by more than 80% with human hepatocytes. We previously reported that the chimeric mice with humanized liver could be useful as a human model in studies on drug metabolism and pharmacokinetics. In the present study, the humanization of an excretory pathway was investigated in the chimeric mice. Cefmetazole (CMZ) was used as a probe drug. The CMZ excretions in urine and feces were 81.0 and 5.9% of the dose, respectively, in chimeric mice and were 23.7 and 59.4% of the dose, respectively, in control uPA–/–/SCID mice. Because CMZ is mainly excreted in urine in humans, the excretory profile of chimeric mice was demonstrated to be similar to that of humans. In the chimeric mice, the hepatic mRNA expression of human drug transporters could be quantified. On the other hand, the hepatic mRNA expression of mouse drug transporters in the chimeric mice was significantly lower than in the control uPA–/–/SCID mice. In conclusion, chimeric mice exhibited a humanized profile of drug excretion, suggesting that this chimeric mouse line would be a useful animal model in excretory studies.
Key Words: biliary excretion; CMZ; renal excretion; transporter.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To clarify the pharmacokinetics of a drug is helpful to evaluate its therapeutic and toxicological effects. The pharmacokinetics is mainly determined by absorption, distribution, metabolism, and excretion. A drug is mostly eliminated by biliary and urinary excretion. To elucidate the excretory pathway of a drug is important for understanding the pharmacokinetics and toxicity. One of the major determinants of the excretory pathway of a drug is thought to be its molecular weight (Hirom et al., 1972
). In general, a drug with high molecular weight is mainly excreted via the bile duct. Recently, several adenosine 5'-triphosphate-binding cassette (ABC) transporters including P-glycoprotein (P-gp) and multidrug resistance–associated protein 2 (MRP2) have been shown to be relevant to biliary excretion (Chandra and Brouwer, 2004; Faber et al., 2003). Various drug interactions in excretory pathways have been reported. Quinidine decreased the biliary clearance of digoxin by 42% in normal healthy human volunteers due to the inhibition of P-gp encoded by multidrug resistance 1 (MDR1) gene (Angelin et al., 1987). Probenecid decreased the clearance of irinotecan hydrochloride and increased the area under the curve of its metabolite by the inhibition of MRP2 in rats (Horikawa et al., 2002). Thus, it is important to predict the drug interactions in excretion for avoiding adverse reactions.
In drug development, experimental animals have been used to predict the human excretory pathway of a drug candidate in preclinical studies. However, urinary recovery has been reported to be different between species in terms of 14C-labeled compounds such as N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine and zenarestat (Tanaka et al., 1992; Tsuda-Tsukimoto et al., 2005). The mechanism of such species differences is unclear, but may be partly due to differences in metabolism and excretion. For patient with liver or renal disease, it may be desirable to select a drug in consideration of its excretory pathway. Therefore, the elucidation of human excretory profile is necessary for preventing the condition to be worsened.
The livers of a chimeric urokinase-type plasminogen activator (uPA)+/+/severe combined immunodeficient (SCID) mouse line established by Tateno et al. (2004) could be replaced by more than 80% with human hepatocytes. We previously investigated the expression of human drug metabolizing enzymes in the liver of the chimeric mice (Katoh et al., 2004, 2005a,b,c). The purpose of the present study is to clarify the excretory profile of a drug and the effect of the replacement with human hepatocytes on drug excretion in the chimeric mice. The clarification of humanized excretion as well as metabolism in the chimeric mice can support an evaluation of the toxicity, especially in liver toxicity. Cefmetazole (CMZ), which is one of the cephalosporin antibiotics, was used as a probe in this excretory study because CMZ is excreted in an unchanged form in humans and rodents. The excretory pathways of CMZ in humans and rats were different. Urinary excretion was dominant in humans (Ko et al., 1989; Welage et al., 1990), whereas biliary excretion was dominant in rats (Murakawa et al., 1980). However, CMZ excretion in mice has not been studied. In our preliminary study, biliary excretion was major in mice as well as rats. Therefore, in the present study, the chimeric mice were employed to investigate the humanized type of excretion.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Materials.
CMZ and cefazolin were purchased from Sigma-Aldrich (St Louis, MO). All primers shown in Tables 2 and 3 were commercially synthesized at Hokkaido System Science (Sapporo, Japan). Human P-gp, human MRP2, rat breast cancer resistance protein (Bcrp), and rat bile salt export pump (Bsep) membranes were obtained from GenoMembrane (Yokohama, Japan) and ABC Transporter ATPase Assay Reagents Kit was purchased from Nacalai Tesque (Kyoto, Japan). All other chemicals were of the analytical or highest grade commercially available.
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Animals.
Animal maintenance and treatment were conducted in accordance with the National Institute of Health Guide for Animal Welfare in Japan, and the present study was approved by the Ethics Committees of Kanazawa University and the Hiroshima Prefectural Institute of Industrial Science and Technology Ethics Board. ICR mice (8 weeks old) were purchased from SLC Japan (Hamamatsu, Japan). Cryopreserved human hepatocytes from a donor (9-month-old, white, male) were purchased from In Vitro Technologies (Catonsville, MD). The chimeric mice were generated by the method described previously (Tateno et al., 2004
). Briefly, uPA+/+/SCID mice at 20–30 days after birth were injected with human hepatocytes through a small left flank incision into the inferior splenic pole. When necessary, the chimeric mice were treated ip with nafamostat mesilate as described by Tateno et al. (2004). The treatment with nafamostat mesilate was discontinued more than 12 h before the excretion study. The concentration of human albumin (hAlb) in the blood of the chimeric mice and the replacement index (RI; the rate of replacement from mice to humans) were measured using an enzyme-linked immunosorbent assay and immunohistochemistry with anti-human specific cytokeratin 8 and 18 antibodies, respectively (Tateno et al., 2004). There was a good correlation between the hAlb concentration and RI (Tateno et al., 2004). The chimeric mice used in the present study were 12- to 17-week-old and exhibited more than 5 mg/ml hAlb concentrations or 60% of RI. The control uPA–/–/SCID mice were obtained as previously reported (Tateno et al., 2004).
CMZ excretion in ICR mice.
To clarify CMZ excretion in mice and evaluate the pathway of administration, ICR mice were ip (n = 6) and iv (n = 6) administered with CMZ in phosphate-buffered saline (PBS) (pH 7.4) at a dose of 25 mg/kg. Urine and feces samples were collected during 24 h after the CMZ administration. The samples were frozen at – 20°C until analysis.
CMZ excretion in chimeric mice.
Chimeric mice (n = 5, Table 1) and control uPA–/–/SCID mice (n = 7) were ip administered with CMZ in PBS (pH 7.4) at a dose of 25 mg/kg. Urine and feces samples were collected during 24 h after the CMZ administration. The samples were frozen at – 20°C until analysis.
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Quantification of CMZ.
The CMZ in urine and feces was quantified using high-performance liquid chromatography (HPLC) (Welage et al., 1990
). Urine samples (0.1 ml) were diluted with 0.4 ml of distilled water. Feces samples were homogenized by Polytoron homogenizer (OMNI international, Marietta, GA) with distilled water and centrifuged at 1,500 x g for 10 min. The diluted urine (0.5 ml) and the supernatant of the feces (0.5 ml) samples were treated with 0.5 ml of 0.5% trichloroacetic acid in methanol containing cefazolin (20 nmol) as an internal standard. After incubation at – 20°C for 20 min, the mixture was centrifuged at 15,000 x g for 10 min. Then the supernatant was diluted 1:1 with 0.1 M citrate buffer (pH 5.4). Aliquots of 50 µl of the sample were injected to the HPLC system with a C30 5-µm analytical column (Develosil, 4.6 x 150 mm; Nomura Chemical, Aichi, Japan). The mobile phase was acetonitrile:0.01 M citrate buffer (pH 5.4) = 8:92 (vol/vol), and the flow rate was 1.2 ml/min. The column temperature was 35°C. The eluate was monitored at 254 nm.
Hepatic RNA extraction and real-time RT-PCR.
Human and mouse transporter mRNAs in chimeric mice were quantified by real-time RT-PCR. Total hepatic RNA was extracted using ISOGEN (Nippon Gene, Tokyo, Japan), and cDNAs were synthesized as described previously (Iwanari et al., 2002). The sequences of primers for human or mouse transporters are shown in Tables 2 and 3, respectively. PCR was performed using the Smart Cycler (Cepheid, Sunnyvale, CA). After initial denaturing at 95°C for 30 s, amplification was started by denaturation at 94°C for 4 s, and then annealing and extension was performed simultaneously. The conditions of the one-step annealing and extension were as follows: human MDR1, human BCRP, human organic anion transporting polypeptide (OATP) 1B1, mouse mdr1, mouse mrp2, mouse organic cation transporter 1 (oct1), and mouse oatp1b2: 64°C for 20 s for 45 cycles; human MRP2: 64°C for 20 s for 35 cycles; human BSEP, human OCT1, human OATP1B3, and mouse bcrp: 66°C for 20 s for 45 cycles; mouse bsep: 60°C for 20 s for 45 cycles.
Amplified products were monitored directly by measuring the increase in the dye intensity of SYBR Green I (Molecular Probes, Eugene, OR) that binds to double-strand DNA amplified by PCR. The copy number of mRNA in the cDNA sample was calculated using the standard amplification curve. It was confirmed that the primers for human and mouse transporters used in this study did not cross-react with mouse mRNA and human mRNA, respectively. The primer set of mouse mdr1 reacts with both mdr1a and mdr1b. For the investigation of mRNA expression of human and mouse transporters, the numbers of the chimeric mice and control uPA–/–/SCID mice used were seven and five, respectively (Tables 4 and 5). For human transporter, the mRNA expression level in chimeric mice was calculated as the relative mRNA expression to the donor hepatocytes (Table 4). For mouse transporter, the mRNA expression level in chimeric mice was calculated as relative mRNA expression to control uPA–/–/SCID mice (Table 5).
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Drug-stimulated transporter ATPase activity assay.
The drug-stimulated transporter ATPase activity was measured using ABC Transporter ATP Assay Reagents Kits as described by Ohashi et al. (2006)
with slight modifications. Briefly, human P-gp, human MRP2, rat Bsep, and rat Bcrp membranes (20 µg) were preincubated at 37°C for 5 min in 40 µl of reaction buffer and CMZ in the presence or absence of 500 µM sodium orthovanadate in 96-well plates. The reaction was initiated by the addition of 20 µl of 12mM MgATP solution and was terminated 30 min later by the addition of 30 µl of stop solution (10 wt/vol% lithium lauryl sulfate). Two hundred microliters of detection reagent (8% ascorbic acid, 0.8% ammonium molybdate, and 3 mM zinc acetate) was added and incubated at 37°C for 20 min. The inorganic phosphate complex was detected by its absorbance at 665 nm and was quantitated by comparing the absorbance with a phosphate standard. The vanadate-sensitive ATP hydrolysis was determined by subtracting the value obtained with the vanadate-coincubated membrane fraction from vanadate-free membrane fraction. |
RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Excretion of CMZ in ICR Mice
By iv administration of CMZ, the means of the 24-h cumulative urinary and fecal excretions were 32.4 ± 4.7 and 63.1 ± 6.6% of the dose, respectively. On the other hand, by ip administration of CMZ, the means of the 24-h cumulative urinary and fecal excretions were 36.9 ± 9.3 and 56.7 ± 8.5% of the dose, respectively. The biliary excretion of CMZ was clarified to be dominant in mice. The 24-h urinary and fecal excretions were similar between iv and ip administrations.
Excretion of CMZ in Chimeric Mice
The recovery of CMZ in urine and feces up to 24 h in chimeric mice is shown in Figure 1. In all of the chimeric mice, the excretion of CMZ in urine was significantly higher than that in feces. On the other hand, in control uPA–/–/SCID mice, the excretion of CMZ in urine was significantly lower than that in feces. The means ± SD of the 24-h cumulative urinary and fecal excretions were 81.0 ± 9.5 and 5.9 ± 4.7% of the dose, respectively, in chimeric mice and 23.7 ± 8.8 and 59.4 ± 11.0% of the dose, respectively, in control uPA–/–/SCID mice. The means of the total CMZ recovery were 86.9 ± 9.4 and 83.2 ± 13.3% of the dose in chimeric mice and the uPA–/–/SCID mice, respectively.
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Expression of Human Drug Transporter in Chimeric Mice
The hepatic mRNA expression of human transporters in the chimeric mice is shown in Table 4. P-gp, BSEP, MRP2, and BCRP can transport a substrate into the bile duct from hepatocytes. OCT1, OATP1B1, and OATP1B3 can uptake a substrate into hepatocytes. Human transporters were expressed in the liver of all chimeric mice used in this study (Table 4). Because the anti-human transporter antibodies commercially available cross-react with mouse orthologous transporters, the protein expression level could not be measured.
Expression of Mouse Drug Transporter in Chimeric Mice
The hepatic mRNA expression of mouse transporters in the chimeric mice is shown in Table 5. The hepatic mRNA expression of mouse mdr1, bsep, mrp2, and bcrp in chimeric mice was 190, 31, 19, and 20% of that in control uPA–/–/SCID mice, respectively. The mRNA expression of mouse oct1 and oatp1b2 in chimeric mice was 4 and 4% of that in uPA–/–/SCID mice, respectively.
Drug-Stimulated Transporter ATPase Activity Assay
The affinity of CMZ to human P-gp and MRP2 was estimated by ATPase activity assay. No stimulation of vanadate-sensitive P-gp or MRP2 ATPase activity was observed up to 2 mM CMZ. Although human BCRP and BSEP membranes could not be obtained, CMZ did not stimulate the ATPase activity in rat Bcrp and Bsep membranes up to 1 mM CMZ.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Understanding the pharmacokinetics could support the efficient and safe evaluation of drug candidates during drug development. However, extrapolation from experimental animals to humans is difficult due to the species differences in absorption, distribution, metabolism, and excretion. There have been many reports that the cumulative excretion of radioactivity in urine and feces was different between species after administration of a 14C-labeled drug (Karim et al., 1976
; Kolis et al., 1976). In the present study, we focused on the species differences in excretion. In the case of CMZ, an unchanged form is mainly excreted. In humans, the cumulated CMZ excretion in urine was 79.7 ± 13.4% of the dose for 72 h after iv administration (Welage et al., 1990) and was 68.8–86.0% of the dose for 24 h after im administration (Ko et al., 1989). On the other hand, CMZ was mainly excreted into bile in rats (Murakawa et al., 1980). In the preliminary study, the major excretory pathway was biliary excretion in ICR mice. Taking this information into consideration, CMZ was selected to investigate the humanization of the excretion pathway in chimeric mice. In humans, CMZ is usually administered iv. In mice, the CMZ excretion showed no significant difference between iv and ip administration. Therefore, excretion after an ip administration of CMZ was measured in the present study. In control uPA–/–/SCID mice, biliary excretion of CMZ was the major pathway, reflecting the species differences in CMZ excretion between humans and mice. In chimeric mice, CMZ was mainly excreted in urine (Fig. 1). The present results suggested that the excretory profile of CMZ was humanized in the chimeric mice. The replacement with human hepatocytes of mouse liver seemed to affect the excretory profile of the drugs.
Recently, many drug transporters have been clarified to play important roles in drug excretion. In the present study, the expression of human and mouse drug transporters was investigated in the chimeric mice. In biliary excretion, the roles of human MDR1, BSEP, MRP2, and BCRP have been well characterized and were shown to be expressed on the canalicular membrane of hepatocytes. Human OCT1, OATP1B1, and OATP1B3 on the sinusoidal membrane, which may be involved in the uptake of a drug into hepatocytes, were also investigated. Human drug transporters were expressed in the liver of the chimeric mice, which was consistent with the previous report by Nishimura et al. (2005). For some human transporters, the relative mRNA expression in the chimeric mice was higher or lower than that in the donor hepatocytes. The mechanism of this phenomenon was unclear. Further study is needed to clarify the expression of human transporters in the chimeric mice generated using hepatocytes from various donors. In addition, the expressions of mouse drug transporters in chimeric mice were measured. Mouse oatp1b2 may correspond to human OATP1B1 (Hagenbuch and Meier, 2004). The expressions of mouse bsep, mrp2, bcrp, oct1, and oatp1b2 mRNAs in chimeric mice were lower than those in control uPA–/–/SCID mice. The mRNA expression of some mouse cytochrome P450 enzymes in chimeric mice was described by Nishimura et al. (2005). The expression ratios of Cyp1a2, Cyp2c9, Cyp2e1, and Cyp3a11 mRNA, of which the mouse mRNA in chimeric mice to that in uPA–/–/SCID mice, were 0.19 or less (Nishimura et al., 2005). Their result was similar to those in our analysis. In the present study, the relative expressions in four out of six mRNAs were 0.20 or less (Table 5). It is presumed that 20% or less of mouse mRNA may be expressed in chimeric mice compared with control uPA–/–/SCID mice. The livers of the chimeric mice used in the present study were replaced approximately 80% by human hepatocytes; therefore, the residue of mouse mRNA was thought to be reasonable. Further study is needed to clarify whether the mouse protein retains its activity. Both the reduction of mouse transporter and the increase of human transporter expressions would be related to the humanization of excretory pattern in the chimeric mice.
The mRNA expression of human BCRP in chimeric mice was higher than that in donor hepatocyte. The mRNA expression of mouse mdr1 in chimeric mice was higher than that in control uPA–/–/SCID mice. These results may be caused by the procedure of the generation of the chimeric mice or the knocking of the uPA gene, but the mechanism is unclear. It was clarified that CMZ was not a human P-gp and rat Bcrp substrate by the measurement of the ATPase activity using human P-gp and rat Bcrp. Therefore, the changes of the CMZ excretory profile in chimeric mice may be independent of the mouse mdr1 and human BCRP mRNA. The drug transporter for CMZ has not been identified yet. However, it should be possible that humanized drug transporters may influence the excretion in the chimeric mice. Although the present study did not investigate the humanization of other factors such as the physiology of liver and bile flow, we keep it in mind to discuss the mechanism.
There are a few reports on the species differences of the expression and substrate specificity in drug transporters. BCRP mRNA could be expressed in both liver and kidney in mice (Jonker et al., 2000; Shimano et al., 2003), but in liver and not in kidney in humans (Doyle et al., 1998). Some compounds exhibited differences in the transport ratio between human and mouse P-gps (Yamazaki et al., 2001). Taking the species differences of drug transporters into consideration, the chimeric mice could make some contribution to the understanding of drug transport involved in the excretion.
In conclusion, the excretory pattern of CMZ could be humanized in chimeric mice, suggesting that the chimeric mice can be useful in studies on drug excretion as well as drug metabolism. Further study concerning drug transporters is needed, but the present study would provide valuable information for applying pharmacological studies using chimeric mice with humanized liver.
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ACKNOWLEDGMENTS |
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This work was supported by a Research on Advanced Medical Technology, Health, and Labor Sciences Research Grant from the ministry of Health, Labor, and Welfare of Japan. We acknowledge Mr Brent Bell for reviewing the manuscript.
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