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Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands
1 Correspondence: Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. E-mail: a.schinkel{at}nki.nl
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: drug metabolism • xenobiotic metabolism • intestinal metabolism • drug-drug interactions • diet
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Both PXR and CAR can be activated by a broad range of xenobiotics, including many drugs. Also food-derived compounds such as dietary phytochemicals can activate PXR and CAR (2)
. In addition to P450s, PXR and CAR are also involved in the regulation of other important detoxifying proteins, such as drug transporters (e.g., P-glycoprotein) (3)
.
Among the P450s, the isoenzyme CYP3A4 is of special interest because it has a very broad substrate specificity. Accordingly, the enzyme is involved in the metabolism of 
50% of the currently marketed drugs (4)
. CYP3A4 is strategically located in the liver and small intestine, where it serves as an important barrier for xenobiotics to enter the systemic circulation. Importantly, CYP3A4 expression levels can vary dramatically due to gene induction or direct inhibition by xenobiotics (5
, 6)
. As a result, the enzyme is a major determinant of variable drug exposure and drug-drug interactions (7)
.
To allow a more systematic in vivo evaluation of CYP3A-mediated metabolism, we have recently generated mice lacking all Cyp3a genes (Cyp3a–/–) (8)
. In addition, we have created transgenic mice with expression of human CYP3A4 in either the intestine or the liver and in a murine Cyp3a knockout background (8)
. Notably, Cyp3a–/– mice are viable and fertile and do not show obvious physiological abnormalities. These observations suggest that the CYP3A enzymes do not have an essential endogenous physiological function and could be primarily dedicated to the detoxification of xenobiotics.
Further characterization of Cyp3a–/– mice revealed that several CYP2C enzymes were up-regulated (9)
. Most prominent was the >30-fold up-regulation of CYP2C55. In this study, we have further investigated the mechanism of CYP2C55 up-regulation. In addition, we extended our studies toward other detoxifying systems that appeared to be up-regulated in Cyp3a–/– mice. By also investigating the regulation of detoxifying genes in hepatic or intestinal CYP3A4 transgenic mice, we discovered an important role for intestinal CYP3A4 in the regulation of detoxifying systems in the liver.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Animals
The mice that were used in this study were housed and handled according to institutional guidelines complying with Dutch legislation. The animals were kept in a temperature-controlled environment with a 12:12-h light/dark cycle and permitted ad libitum consumption of acidified water and a standard (AM-II) diet (Hope Farms, the Netherlands; see Supplemental Table 1), unless indicated otherwise. Mice that were fed with a semisynthetic diet (20% casein, 4068.02; Hope Farms; Supplemental Table 1) received this for at least 2 wk before organs were isolated. Mice used in this study were wild type, Pxr knockout (Pxr–/–) (10)
(kindly provided by Dr. R. M. Evans, Salk Institute for Biological Studies, La Jolla, CA, USA), Cyp3a knockout (Cyp3a–/–), or Cyp3a–/– mice with specific expression of human CYP3A4 in either the liver (Cyp3a–/–A) or the intestine (Cyp3a–/–V) (8)
. All mouse strains were crossed back to obtain a homogeneous (>99%) FVB genetic background, and all experiments were done using male mice that were between 8 and 12 wk old.
PXR and CAR activation in vivo
To assess PXR activation, wild-type and Pxr–/– mice were fed a semisynthetic diet (20% casein, 4068.02; Hope Farms; Supplemental Table 1) for 2 wk. This diet is comparable with the AIN-93G diet and is considered to contain less of inducing agents (e.g., phytochemicals) than the normal AM-II diet (Supplemental Table 1). During the second week, the mice received orally either dexamethasone (25 mg/kg) in corn oil or vehicle for four subsequent days. One day after the last administration, mice were sacrificed, and the organs and subsequently RNA were isolated as described below. For CAR activation, an analogous experiment was carried out. Wild-type mice received intraperitoneal injections with TCPOBOP (3 mg/kg/day) in corn oil for 4 days, while on the same semisynthetic diet.
RNA isolation and cDNA synthesis
Mouse liver and small intestine (duodenum) were excised and immediately placed in an appropriate volume of RNAlater (Qiagen). They were stored at 4°C for several days until RNA was extracted using the RNeasy mini kit (Qiagen) according to the manufacturer’s protocol for the purification of total RNA from animal tissues. Subsequently, cDNA was generated using 5 µg of total RNA in a synthesis reaction using random hexamers (Applied Biosystems, Foster City, CA, USA) and superscript II reverse transcriptase (Invitrogen, Carlsbad, CA, USA), according to the supplier’s protocols. The reverse transcription reaction was performed for 60 min at 42°C with a deactivation step of 15 min at 70°C. cDNA was stored at –20°C until use.
RT-PCR analysis
Real-time RT-PCR was performed using specific primers (Qiagen) for the individual mouse genes on an Applied Biosystems 7500 real-time cycler system according to the manufacturers protocol. Briefly, in a MicroAmp Fast Optical 96-well reaction plate (Applied Biosystems), 25 µl reaction mixtures containing 5 µl cDNA (0.1 ng/µl), 12.5 µl SyBr Green PCR master mix, 2.5 µl sample primer mix (QuantiTect Primer Assays, Qiagen) and 5 µl aqua Braun were pipetted. After sealing the plate with optical adhesive film (Applied Biosystems), the plates were briefly centrifuged. The cycling conditions were initiated at 50°C for 2 min with an enzyme activation step of 95°C for 10 min, followed by 45 PCR cycles of denaturation at 95°C for 15 s, and annealing/extension at 60°C for 1 min. Dissociation curves were analyzed to ensure only a single product was amplified. Analysis of the results was done by the comparative Ct method as described previously (11)
. Briefly, quantitation of the target cDNAs in all samples was normalized to GAPDH cDNA (Cttarget–CtGAPDH=
Ct), and the difference in expression for each target cDNA in the Cyp3a–/– mice was expressed relative to the amount in the wild-type mice (Ctwild-type–CtCyp3a–/–=Ct). Subsequently, fold changes in target gene expression were determined by taking 2 to the power of this number (2–Ct). Statistics were performed on Ct values (12)
. To assess the statistical significance, the two-sided unpaired Student’s t test was used for two group comparisons and one-way ANOVA followed by Dunnett’s posttest for multiple comparisons.
Microsomal incubations
Mouse liver microsomes were prepared as described previously (9)
. Incubations were carried out in a total volume of 200 µl containing 100 mM KPi buffer (pH 7.4) and 0.5 mg/ml liver microsomes. Protein concentrations and incubation times were chosen within the linear range of product formation. Control experiments without cofactor were performed to ascertain CYP-dependent metabolism. After 5 min of preincubation at 37°C, the reactions were initiated with an NADPH-regenerating system (final concentrations 1.3 mM NADP+, 3.3 mM glucose-6-phosphate, 0.4 U/ml glucose-6-phosphate dehydrogenase, and 3.3 mM MgCl2). The reactions were allowed to proceed for 5 min before they were terminated by adding 100 µl of ice-cold acetonitrile, and the mixture was subsequently cooled on ice for 5 min before it was centrifuged (10 min at 6800 g). Fifty microliters of the supernatant was subjected to HPLC analysis.
HPLC analyses
HPLC analyses for midazolam and its 1'-OH metabolites were performed as described before (9)
. Briefly, a Symmetry C18 column (3.0 x150 mm, 3.5 µm; Waters, Etten-Leur, The Netherlands) was used. Isocratic analyses were carried out at a flow rate of 0.4 ml/min. The mobile phase consisted of 33% acetonitrile/23% methanol/44% 10 mM phosphate buffer (pH 7.4; 0.2% triethylamine). The identity of 1'-OH midazolam was verified by comparing the HPLC retention time with an authentic standard. Metabolite was detected at 230 nm and quantitated by comparison with the absorbance of a standard curve for 1'-OH midazolam.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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35-fold) in the liver of Cyp3a–/– mice, both at the mRNA and protein level (9)
. Because PXR and CAR are known to regulate several detoxifying P450 genes, we hypothesized that these nuclear receptors could also be involved in the mechanism of regulation of CYP2C55. We first studied the possible involvement of PXR by administering the prototypical PXR ligand and activator dexamethasone (DEX) to both wild-type and Pxr–/– mice and subsequently determined the CYP2C55 levels by RT-PCR analysis. In DEX-treated wild-type mice, a more than 25-fold increase in hepatic CYP2C55 mRNA levels was observed (Fig. 1A
), suggesting that PXR is involved in the regulation of CYP2C55. No induction after DEX treatment was seen in Pxr–/– mice when compared to untreated Pxr–/– mice, further supporting that the observed induction after DEX treatment is PXR mediated. Note that CYP2C55 mRNA levels were somewhat higher in untreated Pxr–/– compared to wild-type mice, presumably a secondary consequence of the absence of PXR.
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To study whether CYP2C55 expression is also dependent on CAR activation, we administered the prototypical CAR ligand and activator TCPOBOP to wild-type mice. Although we have no Car–/– mice at our disposal, the high specificity of TCPOBOP for CAR allows a good assessment of CAR-mediated gene induction. Interestingly, we observed a roughly 2000-fold induction of CYP2C55 in mice treated with TCPOBOP (Fig. 1B
). Overall, these data indicate that CYP2C55 can be up-regulated by both PXR- and CAR-mediated pathways.
Both intestinal and hepatic expression of CYP3A4 regulates the expression of hepatic CYP2C55 and other hepatic detoxifying systems
We investigated whether transgenic expression of human CYP3A4 could suppress the up-regulation of hepatic CYP2C55 observed in Cyp3a–/– mice. To this end, we used transgenic mice that have either hepatic or intestinal specific CYP3A4 expression in a murine Cyp3a knockout background, denoted as Cyp3a–/–A and Cyp3a–/–V mice, respectively (8)
. The transgenic CYP3A4 activity in liver or intestine of these mouse strains is comparable with the endogenous CYP3A activity in the respective organs of wild-type mice (8)
, indicating physiologically relevant levels of CYP3A4. As illustrated in Fig. 2A
, CYP2C55 RNA was up-regulated (40-fold) in the liver of Cyp3a–/– mice and CYP3A4 transgenic expression in the liver (Cyp3a–/–A) was able to restore close to normal levels for CYP2C55. Strikingly, also in mice that have specific transgenic CYP3A4 expression in the intestine but not in the liver (Cyp3a–/–V), expression levels for CYP2C55 in the liver were restored to normal (Fig. 2A
).
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To determine whether this expression pattern between the mouse strains is exclusive for CYP2C55 or holds true for more detoxifying systems that are regulated by PXR and CAR, we investigated a number of other genes by RT-PCR. We selected genes for detoxifying systems based on the hepatic up-regulation observed in a previous microarray analysis of Cyp3a–/– mice (8)
. Accordingly, it appeared that CYP2B10, CYP2C29, Mdr1a, Mrp3, and Oatp1a4 (previously Oatp2) RNAs were up-regulated in the liver of Cyp3a–/– mice (Figs. 2B
and 4B
). Expression of human CYP3A4 in either the liver or intestine prevented the hepatic up-regulation, and in several cases even caused a down-regulation when compared to wild-type mice (Fig. 2B
). These results are qualitatively similar to those observed for CYP2C55, and confirm a strong effect of not only hepatic but also intestinal CYP3A4 on hepatic expression of detoxifying genes up-regulated in Cyp3a–/– mice.
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In addition to the liver, we also investigated differences in CYP2C55 mRNA levels between the various mouse strains in the duodenum part of the small intestine. Although less pronounced than in the liver, a significant up-regulation of CYP2C55 was also observed in the intestine of Cyp3a–/– mice (Fig. 3A
). Notably, whereas liver expression of CYP3A4 did not affect the intestinal CYP2C55 up-regulation as seen in Cyp3a–/– mice, CYP3A4 expression in the intestine resulted in a marked down-regulation of intestinal CYP2C55 when compared to wild-type mice. Intestinal mRNA expression levels of CYP2B10, CYP2C29, and Mdr1a were not significantly altered in Cyp3a–/– mice and Mrp3 showed only a modest induction. Yet, the intestinal expression of CYP2B10, CYP2C29, and Mdr1a was markedly down-regulated in mice with intestinal specific expression of CYP3A4 (Cyp3a–/–V), whereas Mrp3 returned to near wild-type levels. The intestinal levels of CYP2B10 and Mdr1a were also significantly down-regulated in mice with hepatic CYP3A4 expression (Cyp3a–/–A). Oatp1a4 is not significantly expressed in the intestine (13)
and therefore not included in the intestinal analysis.
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Dietary compounds are responsible for the strong induction of detoxifying systems in the absence of CYP3A
We hypothesized that CYP3A normally metabolizes one or more activators of PXR, CAR, and/or other nuclear xenobiotic receptors and that consequently levels of these activators are much higher in Cyp3a–/– mice. An obvious source of such activators are xenobiotics (e.g., phytoestrogens or other phytochemicals) that occur in the standard chow of our mice, which contains several comparatively crude plant-derived ingredients such as alfalfa hay, wheat, linseed, and oats (Supplemental Table 1). We therefore tested the effect of replacing the standard chow with a semisynthetic diet that contains far less plant-derived components (Supplemental Table 1). Indeed, we then found markedly lower induction levels (5-fold instead of 42-fold) of CYP2C55 mRNA in the liver of Cyp3a–/– mice compared to wild-type mice (Fig. 4A
), albeit that no complete return to wild-type levels was seen. Similarly, also the induction of CYP2B10 and Oatp1a4 in the liver of Cyp3a–/– mice was reduced on the semisynthetic diet compared to the standard diet, and expression levels of CYP2C29, Mdr1a and Mrp3 were even unaltered by the absence of CYP3A on semisynthetic food (Fig. 4B
). Collectively, these data indicate that food-derived xenobiotics, which are normally metabolized by CYP3A, are a major factor in the hepatic up-regulation of several detoxifying systems in Cyp3a knockout mice. It should be noted that replacing standard by semisynthetic diet also reduced CYP2C55 expression by 4-fold in wild-type mice (Fig. 5
), indicating a significant inducing effect of standard food, even in the presence of endogenous CYP3A. Similarly, in wild-type mice also the hepatic expression levels of the murine CYP3A11 and CYP3A25 genes, as well as CYP2C29 and Oatp1a4, were reduced by 1.5- to 3-fold on the semisynthetic diet (Fig. 5)
.
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Semisynthetic diet reduces midazolam metabolism in wild-type and Cyp3a–/– mouse liver microsomes
We have previously shown that the CYP3A model substrate midazolam is still efficiently metabolized in Cyp3a–/– mice as a result of up-regulated CYP2C enzymes (9)
. We therefore tested whether the reduced level of CYP2C in Cyp3a–/– mice receiving the semisynthetic diet (as compared to mice on regular diet) is also reflected in demonstrably altered metabolism. We performed incubations with liver microsomes from wild-type and Cyp3a–/– mice that had been given either standard or semisynthetic diet and studied the metabolism of midazolam by measuring 1'-OH midazolam formation (Fig. 6
). Whereas the 1'-OH midazolam formation was reduced by 1.7-fold in wild-type mice that had received the semisynthetic diet, it was reduced by 3-fold in Cyp3a–/– mice. This 3-fold diet-dependent reduction in midazolam metabolism in Cyp3a–/– mice is qualitatively consistent with the reduced hepatic CYP2C RNA levels (Fig. 4A, B
). The (smaller) reduction seen in wild-type mice can probably be attributed to reduction of both CYP3A and CYP2C RNA levels (Fig. 5)
.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), but also indirectly the expression levels of a broad range of other detoxifying systems. Finally, also the induction level of detoxifying systems in the intestine is importantly reduced by intestinal CYP3A4 activity. Given the diversity and potential impact of the detoxifying systems affected, our findings suggest that intestinal CYP3A activity can have far-reaching biological effects.
Among the 15 mouse Cyp2c genes, it has been shown that the induction of CYP2C29 and CYP2C37 can be mediated by CAR (14
, 15)
. However, CYP2C44 could not be up-regulated by either PXR or CAR activators (16)
. Thus far, the role of PXR and CAR in the regulation of CYP2C55 has not been addressed. In this study, we demonstrated that activation of both CAR and PXR results in an up-regulation of CYP2C55. However, given the very high up-regulation seen after TCPOBOP treatment, CAR-mediated induction seems more likely to be an important determinant in the regulation of CYP2C55. These results indicate that also in Cyp3a–/– mice, PXR and/or CAR could be involved in the up-regulation of CYP2C55. Moreover, since PXR and CAR regulate a wide variety of detoxifying genes, it could be expected that more target genes of these nuclear receptors are altered in Cyp3a–/– mice. Indeed, we demonstrated that not only CYP2C55 but also CYP2B10, CYP2C29, Mdr1a, Mrp3, and Oatp1a4 are up-regulated in the liver of Cyp3a–/– mice.
Since CYP2C55 is up-regulated in Cyp3a–/– mice, we hypothesized that transgenic expression of CYP3A4 could compensate for the loss of murine CYP3A activity and that consequently expression levels of CYP2C55 would be normalized. Interestingly, the induction of CYP2C55 observed in the liver of Cyp3a–/– mice was reversed not only in transgenic mice with liver-specific CYP3A4 expression (Cyp3a–/–A) but also in mice that only have intestinal CYP3A4 expression (Cyp3a–/–V). This suggests that CYP3A functionality in the intestine is important for limiting hepatic (and systemic) exposure to orally ingested inducing agents and thereby regulating the induction pattern of CYP2C55 in the liver. In contrast, expression of CYP3A4 in the liver did not influence the expression of intestinal CYP2C55, whereas intestinal CYP3A4 expression did result in reduced intestinal CYP2C55 levels. This suggests that local intestinal exposure to CYP2C55-inducing compounds (e.g., PXR/CAR activators) is determined by intestinal CYP3A activity rather than hepatic. Importantly, our results demonstrate that intestinal CYP3A activity is not only relevant for the regulation of hepatic CYP2C55 but also for a range of other hepatic detoxifying systems such as CYP2B10, CYP2C29, Mdr1a, Mrp3, and Oatp1a4. We note that in some cases, transgenic CYP3A4 expression did not only normalize expression levels of the target genes but even reduced them compared to wild type. This might be caused by species differences in catalytic properties between mouse and human CYP3A toward the (dietary) inducers. Also subtle differences in effective expression levels between the mouse CYP3A enzymes and the transgenic CYP3A4 enzyme could be partly responsible for this.
It is known that many dietary phytochemicals can activate PXR and CAR (2)
. Clearly, the CYP3A-mediated breakdown of phytochemicals is absent from Cyp3a–/– mice. It is, therefore, likely that levels of a number of inducing phytochemicals are higher in Cyp3a–/– mice and that consequently PXR, CAR, and possibly other xenobiotic nuclear receptors are more activated in these mice. Indeed, we demonstrated that when mice were given a semisynthetic diet containing lower levels of phytochemicals, the induction of several detoxifying systems in Cyp3a–/– mice was markedly reduced. With this result, the importance of intestinal CYP3A activity in the regulation of hepatic detoxifying systems can be readily explained: the inducing compounds are mainly food derived, yielding immediate exposure of intestinal epithelial cells irrespective of hepatic metabolism. Nevertheless, although our study shows a prominent role for food-derived compounds in the up-regulation of detoxifying systems in Cyp3a–/– mice, a significant contribution of endogenous inducers (e.g., bile acids, steroids) cannot be excluded. Indeed, although the induction of CYP2C55 in Cyp3a–/– mice was much less pronounced on the semisynthetic diet, there was still a significant increase when compared to wild-type mice that had been given the same chow (Fig. 4A
). We further note that semisynthetic diets may affect bile-acid synthesis and/or metabolism, thereby altering detoxifying systems (e.g., 17
). We, therefore, cannot exclude that some of the effects of the diet change could be due to altered bile acid levels. Clearly, the identification of the dietary (and/or endogenous) inducing compounds will be of interest, but difficult, especially as it is likely that several compounds work in concert, each possibly activating different nuclear receptors and corresponding target genes, making the assessment of individual contributions complicated.
We have previously demonstrated that the CYP3A probe drug midazolam is still efficiently metabolized in Cyp3a–/– mice as a result of up-regulated CYP2C enzymes (9)
. Here, we show that when mice were given a semisynthetic diet, the microsomal formation of 1'-OH midazolam was reduced more in Cyp3a–/– than in wild-type mice, directly illustrating the relevance of the expression changes at the drug metabolism level. This change is qualitatively in accordance with the reduced levels of CYP2C enzymes in Cyp3a–/– mice receiving the semisynthetic diet. Clearly though, the strong (more than 30-fold) reduction in CYP2C55 RNA expression levels seen on semisynthetic diet (Supplemental Table 2) is not completely reflected in the 1'-OH midazolam formation data. We note, however, that, on the basis of turnover rates and absolute RNA expression levels, CYP2C29 rather than CYP2C55 is likely to be the major enzyme responsible for the 1'-OH midazolam formation in Cyp3a–/– mice (9)
. Indeed, quite consistent with the 3-fold reduced 1'-OH midazolam formation (Fig. 6)
, absolute CYP2C29 RNA levels were 2.8-fold reduced in Cyp3a–/– mice due to semisynthetic diet feeding (Supplemental Table 2).
In addition to PXR- and CAR-mediated induction, activation of the arylhydrocarbon receptor (AhR) is also known to regulate important detoxifying systems such as CYP1A1. To activate target genes, AhR has to form a heterodimer with the AhR nuclear translocator (Arnt). Recently, Ito et al. (18)
have reported that dietary phytochemicals can regulate the expression of CYP1A1 in the liver and other organs via an Arnt-dependent system in the gut. By studying a mutant mouse in which the Arnt gene was specifically disrupted in the gut, they found that CYP1A1 expression levels were up-regulated in liver, as well as in several other nongut tissues (18)
. In addition, they found that the CYP1A1 up-regulation was lost on administration of a semisynthetic diet. For unknown reasons, the up-regulation was CYP1A1 selective and was not observed for other prototypical AhR target genes. Although this mechanism of regulation is different from the one reported here, it also demonstrates the importance of intestinal metabolism of xenobiotics in the regulation of a hepatic detoxifying system. Clearly though, our present study shows that intestinal CYP3A activity has a much broader biological effect as it can regulate a range of detoxifying systems rather than one.
We have recently utilized the transgenic Cyp3a–/– mice expressing human CYP3A4 in either the intestine or the liver to determine the relative importance of intestinal vs. hepatic CYP3A4 activity in first-pass drug metabolism. These studies revealed that intestinal CYP3A4 alone was sufficient to virtually abrogate docetaxel entry from the gut, whereas hepatic CYP3A4 was more important in systemic docetaxel clearance (8)
. This study clarified the potential significance of intestinal metabolism, which has been a matter of debate for decades (19
20
21)
. In addition to this, our present study reveals an important role for intestinal CYP3A4 activity in the regulation of detoxifying systems in the liver. It seems likely that, like docetaxel, food-derived inducing compounds are efficiently extracted and degraded by CYP3A4 already at the level of the enterocyte, preventing significant exposure of the liver. Although our studies are done in mice, this concept is likely to be relevant for the human situation as well. As such, specific inhibition of intestinal CYP3A4 activity by, for example, grapefruit juice (22)
could result in higher levels of detoxifying systems (including CYP3A) in the liver. Also, people with high intestinal CYP3A levels, could have lower levels of hepatic detoxifying systems and vice versa. Accordingly, this would mean that intestinal and hepatic expression levels of CYP3A (but also of other detoxifying systems) do not always correlate or may at times even be inversely correlated. Indeed, several clinical studies have indicated that individuals with low intestinal CYP3A activity have relatively high hepatic CYP3A activity (23
24
25)
. Although more (clinical) evidence has to be provided in favor of such an inverse relationship, it could have important implications for the prediction of drug exposure.
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ACKNOWLEDGMENTS |
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Received for publication July 1, 2008. Accepted for publication August 14, 2008.
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REFERENCES |
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