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Journal of Clinical Pharmacology, 2004; 44:481-486
© 2004 the American College of Clinical Pharmacology

MOLECULAR PHARMACOLOGY

MDR1 mRNA Expressions in Peripheral Blood Mononuclear Cells of Patients with Ulcerative Colitis in Relation to Glucocorticoid Administration

Toshihiko Hirano, PhD, Kenji Onda, BS, Tsugutoshi Toma, BS, Masaaki Miyaoka, MD, Fuminori Moriyasu, MD and Kitaro Oka, PhD

From the Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan (Dr. Hirano, K. Onda, T. Toma, Dr. Oka); Gastroenterology Department of Internal Medicine, Hachioji Medical Center, Tokyo, Japan (Dr. Miyaoka); and 4th Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.

Address for reprints: Toshihiko Hirano, PhD, Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Overexpression of multidrug resistance (MDR) protein, P-glycoprotein (P-gp), on lymphocytes has been suggested to be implicated in the failure of glucocorticoid (GC) therapy in patients with ulcerative colitis (UC). However, whether the overexpression of P-gp in a class of patients with inflammatory bowel disease (IBD) is intrinsic or related to the administration of GC is unknown. Relative amounts of MDR1 mRNA expressed in peripheral blood mononuclear cells (PBMCs) were measured using the reverse-transcriptase polymerase chain reaction (RT-PCR) technique in 25 UC patients having no history of GC administration, 25 UC patients having experienced GC therapy, 19 patients with Crohn's disease (CD) with no history of GC therapy, and 27 healthy subjects. Relative amounts of MDR1 mRNA expressed in PBMCs were compared among the groups. The relationship between the amounts of MDR1 mRNA expressed, as well as the total dose of GC administered or the period of GC therapy in UC patients, was examined. The relative amounts of MDR1 mRNA expressed in PBMCs were not significantly different between the healthy subjects and CD patients or UC patients having no history of GC therapy. However, the mean MDR1 mRNA amount in PBMCs of UC patients having experienced GC therapy was significantly greater than that in PBMCs of UC patients with no history of GC administration (p = 0.0375). The amounts of MDR1 mRNA in PBMCs of UC patients having experienced GC therapy significantly correlated with the total dose of GCs administered (p = 0.0175). Overexpression of MDR1 mRNA in PBMCs of IBD patients is not intrinsic. However, high-dose administration of GCs for the treatment of UC may result in an increased expression of MDR1 mRNA, which may impair successful GC therapy in these patients.

Key Words: P-glycoprotein • glucocorticoid therapy • ulcerative colitis • inflammatory bowel disease • peripheral blood mononuclear cells

P-glycoprotein (P-gp), the product of the multidrug resistance (MDR) gene, is a transmembrane efflux pump for different lipophilic compounds, including many anticancer drugs.1-3 Intracellular drug accumulation in cells expressing functional P-gp has been found to decrease as a result from drug efflux.4 Thus, many reports have described the involvement of multi-drug-resistant P-gp expression in cancer cells in the development of chemoresistance.5-7 P-gp overexpression has also been reported in peripheral blood mononuclear cells (PBMCs) of ulcerative colitis (UC) patients who are refractory to glucocorticoid (GC) therapy as compared to PBMCs in patients who have responded well to GC therapy.8 Thus, the overexpression of P-gp on PBMCs has been suggested to be implicated in the failure of GC therapy in the treatment of UC.8 Therefore, the monitoring of P-gp overexpression in PBMCs may provide efficient information for carrying out successful GC therapy in the treatment of UC. However, whether the overexpression of P-gp in PBMCs in a certain class of UC patients is intrinsic or related to the administration of GCs for the treatment of UC is not well understood.

In this study, we measured the relative amounts of MDR1 mRNA in PBMCs of the following patients with inflammatory bowel disease (IBD): those who had no history of GC administration and those who had experienced GC therapy. Relative amounts of MDR1 mRNA expressed in PBMCs were compared among the groups. Furthermore, the relationship between the amounts of MDR1 mRNA expressed in PBMCs, as well as the total dose of GC administered or the total period of GC therapy, was examined.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
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Subjects
The study included 25 UC patients with no history of GC therapy (15 male and 10 female; age 39.2 ± 11.4 years), 25 UC patients having experienced GC therapy (10 male and 15 female; age 35.6 ± 10.7 years), 19 Crohn's disease (CD) patients (15 male and 4 female; age 30.6 ± 7.1 years), and 27 healthy subjects (13 male and 14 female; age 32.9 ± 10.1years).Among the 25 UC patients having experienced GC therapy, 13 were under GC therapy on the day of blood sampling (90-1035 days from the beginning of GC therapy), while 12 patients had experienced 25 to 1050 days of GC therapy until 5 to 18 months before blood sampling. The diagnosis of UC and CD was established based on endoscopic and histological criteria as well as clinical symptoms. In addition, the healthy subjects had no history of immunosuppressive medication. The patients had no complications or history of immunological disorders other than UC or CD. None of the CD patients or healthy subjects had been administered GCs. Subject profile and the data for MDR1 mRNA expressions in PBMCs of these patients and healthy subjects are included in Table I.


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  		Table I Subject Profiles and the Data for MDR1 mRNA Expression in PBMCs

 

GC Therapy and Evaluation of Clinical Status in UC Patients
As described above, 25 UC patients had experienced GC therapy. Of these 25 patients, 14 were administered oral or intravenous prednisolone, while the other 11 were administered betamethasone suppositories. The starting dose for oral prednisolone in the above UC patients was 30 to 80 mg/day, and thereafter the dose was reduced gradually. In the case of patients with mild to moderate UC (20 of 25 patients), the starting dose of oral prednisolone was 30 to 40 mg/day, whereas in the case of patients with severe UC (5 patients), the dose was 40 to 80 mg/day. Intravenous prednisolone administration was carried out for patients with severe UC with a dose of 1 to 1.5 mg/kg/day. The dose was further tapered over 3 months but occasionally changed according to the clinical conditions of the patients. UC clinical activity was assessed with general evaluation procedures, including daily stool frequency, bloody stool frequency, abdominal pain, and so on. Extent of the disease or medication history, assessed by total dose of prednisolone, period of prednisolone administration, and side effects possibly related to prednisolone, was monitored, and relationships between these clinical indications and MDR1 mRNA expressions in PBMCs were investigated.

Isolation of Peripheral Blood Mononuclear Cells
After informed consent was obtained, 20 mL of venous blood was taken from patients with UC or CD and healthy subjects at 9:30 to 11:00 a.m. and heparinized. The heparinized blood was loaded on 6 mL of Ficoll-Hypaque (Nakarai Co., Japan) and centrifuged at 1300g for 15 minutes, and PBMCs were separated as described previously.9-11 The cells were washed and re-suspended in phosphate-buffered saline to a cell density of 1 x 106 cells/mL.

Detection of MDR1 mRNA
Expression of MDR1 mRNA in PBMCs was determined by reverse transcription of poly(A)+RNA followed by polymerase chain reaction analysis (RT-PCR), as we reported previously.12

In brief, poly(A)+RNA from PBMCs as prepared above was isolated by the Quick PrepTM Micro mRNA Purification Kit (Amersham Pharmacia Biotech, CITY?) according to the manufacturer's instructions. The cDNA was synthesized by reverse transcription in a 25-µL buffer containing 1 x TaqMan RT buffer, 5.5 mM MgCl2, 500 µM of each dNTP, 2.5 µM of random hexamer, 0.4 U/µL of ribonuclease (RNase) inhibitor, and 1.25 U/µL of MultiScribe reverse transcriptase (Applied Biosystems, CITY?, Japan). The PCR was performed using real-time SYBR green technology and analyzed by an ABI 7700 sequence detector (Applied Biosystems). Primer sequences for MDR1 were 5'-GGCCTAATGCCGAACACATT-3' and 5'-CAGCGTCTGGCCCTTCTTC-3'. Primer sequences for glyceraldehyde triphosphate dehydrogenase (GAPDH) were 5'-GAAGGTGAAGGTCGGAGTC-3' and 5'-GAAGATGGTGATGGGATTTC. To prepare the calibration concentration curve, lambda DNA amplicon (140 bp) was constructed by PCR using lambda DNA-specific primer pairs. A calibration curve was obtained using 1:10 dilutions of a lambda DNA template (Takara, Kyodo, Japan). The quantity of the MDR1 mRNA and GAPDH transcript in each sample was determined from the calibration curve. To compare the expression level of MDR1 mRNA between subjects or subject groups, the ratio of the MDR1 transcript to the GAPDH transcript was calculated. The mean of the duplicate was shown in each case. The PCR products were subjected to 2% agarose gel electrophoresis to ensure that no unspecific amplicon was obtained. To further confirm their sequences, the resultant PCR products were applied to the sequencing reaction.

Statistical Analysis
Fisher's exact probability test was used for comparison of the proportion of subjects with given characteristics between the subject groups. The Kruskal-Wallis test was conducted to examine differences in the expression levels of MDR1 mRNA among the four subject groups (i.e., UC patients with no history of GC therapy, UC patients having experienced GC therapy, CD patients, and healthy subjects) or among the UC patient subgroups who were divided based on the location of disease. The amounts of MDR1 mRNA in PBMCs were also compared between UC patients with no history of GC therapy and those having experienced GC therapy by the Mann-Whitney U-test. Comparison of MDR1 mRNA amounts between two subgroups of UC patients having experienced GC therapy was also carried out by the Mann-Whitney U-test. Correlations between MDR1 mRNA content in PBMCs and some clinical values or other data for UC patients, including the mean daily dose of GCs, the total dose of GCs, and the period of GC administration, were analyzed with Pearson's correlation coefficient test. The log values of the amounts of MDR1 mRNA were used for these analyses. These analyses were performed with Statview.13 In each case, two-sided p-values less than 0.05 were considered to be significant.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Comparison of MDR1 mRNA Amounts in PBMCs between IBD Patients and Healthy Subjects
The data for MDR1 mRNA amounts expressed in PBMCs in each subject are shown in Figure 1. The means (SDs) of relative amounts of MDR1 mRNA, as compared to the amounts of the GAPDH transcript (x 10-3) expressed in PBMCs of healthy subjects, CD patients, UC patients having no history of GC therapy, and UC patients having experienced GC therapy, were 34.1 (29.9), 32.7 (26.7), 32.9 (26.6), and 56.5 (51.7), respectively. Profiles of the subjects included in this study and the data for mean (SD) and median (range) of the amounts for MDR1 mRNA expressed in PBMCs are presented in Table I. The relative amounts of MDR1 mRNA were not significantly different between healthy subjects and CD patients or UC patients having no history of GC therapy. However, the MDR1 mRNA amount in PBMCs of UC patients having experienced GC therapy was significantly greater than that in PBMCs of UC patients having no history of GC therapy (p = 0.0375 by the Kruskal-Wallis test) (Figure 1). Comparison of the MDR1 mRNA amount in PBMCs between UC patients under GC therapy and the patients with no history of GC therapy by the Mann-Whitney U-test supports this difference (p = 0.0110). The number of patients with moderate to severe symptoms of UC who had not had GC therapy was 2 out of 25 (8%), which was not significantly different from the number of patients who had GC therapy (5/25; 20%).



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  		Figure 1. Comparison of amount of MDR1 mRNA expression in peripheral blood mononuclear cells (PBMCs) between healthy subjects (n = 27), Crohn's disease (CD) patients (n = 19), ulcerative colitis (UC) patients having no history of glucocorticoid (GC) therapy (n = 25), and UC patients having experienced GC therapy (n = 25). Statistically significant difference was observed by the Kruskal-Wallis test (p = 0.0375).

 

Relationship between MDR1 mRNA Expression in PBMCs and Clinical Profiles or Laboratory Data in UC Patients with a History of GC Therapy
The MDR1 mRNA amounts expressed in PBMCs of UC patients having experienced GC therapy showed large individual deviations as compared to the amounts in PBMCs of other subject groups, as can be seen in Figure 1. Then, we further examined the relationship between the MDR1 mRNA amounts in PBMCs and the clinical profiles or laboratory data in these 25 UC patients.

The amounts of MDR1 mRNA are significantly correlated with the total doses of GCs administered (p = 0.0175) (Figure 2), while the periods of GC administration for the treatment of UC in these patients did not correlate significantly with the MDR1 mRNA amounts (r = 0.374, p = 0.0656). The mean daily doses of GCs in these patients also did not correlate significantly with the MDR1 mRNA amounts (r = 0.152, p = 0.4728). When these patients were divided into three subgroups according to their levels of disease progression of UC—that is, total colitis type (n = 14), left-side colitis type (n = 6), and proctitis type (n = 5)—the median (range) MDR1 mRNA amounts (per GAPDH mRNA amounts x 10-3) were 34.5 (12.5-254.1), 44.1 (14.9-80.0), and 55.3 (21.3-79.8), respectively, and no significant difference in mRNA amounts was observed between these subgroups. Similarly, the median (range) MDR1 mRNA amount in PBMCs of patients in a remission stage was 28.8 (14.9-151.5) (n = 7), which was not significantly different from that in PBMCs of the patients in an active stage (median = 55.7, range = 21.0-254.1; n = 12). The median MDR1 mRNA amount was also compared between patients with mild disease severity (n = 20) and those with moderate to severe disease severity (n = 5), but no significant difference was observed between these subgroups (40.6 vs. 43.8). The median (range) amount of the transcripts in patients treated with oral or intravenous GC was 44.4 (14.9-254.1; n = 14), which was not significantly different from that in patients treated with suppository GC (median = 39.3, range = 12.5-80.0; n = 11). There was no significant correlation between the amounts of MDR1 mRNA in PBMCs and the duration (period) of disease in these patients (data not shown).



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  		Figure 2. MDR1 mRNA expressions in 25 ulcerative colitis (UC) patients having experienced glucocorticoid (GC) therapy in relation to total doses of GCs used for their therapy.

 


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present study was undertaken to examine whether MDR1 mRNA overexpression in PBMCs of IBD patients is intrinsic or related to GC therapy. Since overexpression of MDR1 mRNA in PBMCs of UC patients has been suggested to be implicated in an undesirable outcome of patients when treated with GC,8 it would be advantageous to know the status of P-gp and/or MDR1 mRNA expression in PBMCs before administration of GCs for successful GC therapy in these patients. The data described above suggest that the amounts of MDR1 mRNA expressed in PBMCs of UC patients before GC therapy were not intrinsically different from those of healthy subjects. The data also suggest that the expression levels of MDR1 transcript in PBMCs of CD patients having no experience of GC administration are normal. However, the amounts significantly increased after treatment with GCs in UC patients, and the increase in the amounts of MDR1 mRNA suggests a relationship with total GC doses. In contrast, administration of other drugs usually applied for IBD treatment, including salazosulfapyridine and 5-aminosalicylic acid, suggests no significant influence on MDR1 mRNA expressions in PBMCs of UC patients. Attenuation of the efficacy of GCs and the refractory of IBD symptoms is known to often occur during long-term GC therapy in IBD, and such clinical observations may be explained with the data shown here.

The relationship between the MDR1 mRNA/functional P-gp expressions and the cellular or clinical resistance to anticancer drugs is still controversial,14-18 but data from many of the studies support the existence of such a correlation.15-18 From this point of view, the amount of P-gp expressed on immune cells might also influence the therapeutic efficacy of GCs, which are known as substrates of P-gp.19 Overexpression of functional P-gp or MDR1 mRNA has been reported to be induced by mutation of a tumor suppressor p53 gene20 or by stimulation of cells by inflammatory chemical mediators such as TNF{alpha}.21,22 In addition to these tissue or cellular factors, induction of P-gp or MDR1 mRNA in cancer cells by several anticancer agents has been suggested.16-18 Similar observations were also made in PBMCs of patients with rheumatoid arthritis who had received relatively long-term prednisolone therapy.23 On the other hand, cyclosporine was reported to induce P-gp expressions in cultured endothelial and tubule cells24 or in kidney allografts.25 Our present data suggest that the baseline characteristics of the patients and disease extension, activity, or severity of UC do not significantly influence the amount of MDR1 mRNA in PBMCs of UC patients, while prolonged GC therapy increases the risk of induction of MDR1 mRNA overexpression, which might result in clinical GC resistance in these patients. However, the administration route of GCs (i.e., oral, intravenous, or suppository) appeared to have little influence on the significant increase of MDR1 mRNA in PBMCs of the present UC patients. Since the amount of MDR1 expressed in PBMCs of UC patients has been suggested to be persistently unchanged after discontinuation of GC administration,8 our observations raised the point that efficient therapy at the early stage of GC administration is especially important for successful GC treatment in UC. Immunosuppressive drugs having inhibitory activity against P-gp function such as cyclosporine or tacrolimus,26 in addition to or instead of GCs, would be possible candidates as efficient strategies for overcoming GC resistance in UC patients who have exhibited overexpression of MDR1 mRNA by high-dose exposure to GC.

The present data, in conclusion, suggest that overexpression of MDR1 mRNA in PBMCs of IBD patients is neither intrinsic nor developed in relation with the disease progression itself. However, high-dose administration of GCs for the treatment of UC results in increased expression of MDR1 mRNA in PBMCs, which may impair successful GC therapy in these patients.


   FOOTNOTES
 
DOI: 10.1177/0091270004264162

This study was supported by a grant-in-aid for Scientific Research from the Ministry of Education and Science, Japan (grant number 13672402).

Submitted for publication August 20, 2003; Revised version accepted January 30, 2004.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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