* Xenogen Corporation, Alameda, California 94501; Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; and
Xenogen Biosciences, Cranbury, New Jersey 08512
Received April 15, 2004; accepted August 12, 2004
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ABSTRACT |
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Key Words: cytochrome P450 1A2; transgenic mice; aryl hydrocarbon receptor; drug metabolism; xenobiotics; luciferase; reporter, imaging; gene regulation.
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INTRODUCTION |
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The expression and regulation of CYP 1A genes among mammals is quite similar (Okey et al., 1994). The Cyp1a2 gene is constitutively expressed in liver, while the Cyp1a1 is expressed in several tissues only after induction in mice (Kimura et al., 1986
). The mouse Cyp1b1 is constitutively expressed in liver, lung, and uterus (Savas et al., 1994
). Studies on the regulation of CYP1 genes have mainly focused on the CYP1A1 isoform. Regulation of the CYP1A2 gene is not clearly understood in mammals. Aryl hydrocarbons (Ah) such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), ß-naphthoflavone (BNF), and 3-methylcholanthrene (3-MC) induced the mouse Cyp1a genes through a classic aryl hydrocarbon receptor (AhR) signaling pathway requiring interaction with AhR nuclear translocator (ARNT) and heat shock protein 90 (HSP90) (Tukey and Nebert, 1984
). Some other compounds such as acenaphthylene, piperonyl butoxide, and phenobarbital utilize unidentified AhR-independent mechanisms in mice to induce Cyp1a2 gene (Ryu et al., 1996
; Sakuma et al., 1999
). The human CYP1A2 promoter has been partially characterized. A response element including an AhR binding site and two AP1 sites have been identified approximately 2.2 kb upstream of the transcription start site of the human CYP1A2 gene (Quattrochi et al., 1998
). Nuclear factor-1, CCAT transcription factor, nuclear factor 1-like, and hepatic nuclear factor-1 binding sites and six E-box motifs in the human CYP1A2 promoter region are required for tissue-specific and constitutive expression (Chung and Bresnick, 1995
; Pickwell et al., 2003
; Zhang et al., 2000
).
We have previously used bioluminescent imaging approach to study in vivo transcription of the CYP3A4 gene in mice (Zhang et al., 2003, 2004
). Since regulation of the CYP3A4 gene through orphan nuclear receptors such as pregnane X receptor and constitutive androstane receptor is so different from the CYP1A gene regulation through the AhR receptor, it is necessary to establish an in vivo model to study transcriptional effects of Ah on the CYP1A genes. The constitutive level of Cyp1a2 mRNA appears to be at least as high as the maximally induced mRNA level of Cyp1a1 (Gonzalez et al., 1984
). As a result, a smaller induction of Cyp1a2 over a high basal level can lead to a greater increase in the activation of carcinogens and clearance of drugs than that due to Cyp1a1 maximal induction. Due to the importance of Cyp1a2 induction and because the outbred CD-1 mouse strain is the most common mouse strain used in toxicology studies, we developed a transgenic model [Crl:CD-1(ICR)BR-Tg(Cyp1a2-luc)Xen] containing an 8.4-kb mouse Cyp1a2 promoter driving a luciferase reporter in the CD-1 mouse background. Basal expression of the transgene mimics the endogenous Cyp1a2 gene distribution in the transgenic mice. Both Ah and non-Ah compounds induced the reporter transgene in vivo. This model provides a unique tool to examine chemical compounds that may induce the mouse Cyp1a2 gene in a low-responsive strain.
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MATERIALS AND METHODS |
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Genotyping of Cyp1a2-luc transgene. Transgenic founders and offspring were identified by polymerase chain reaction (PCR) using luciferase primers Luc F (5'-GAAATGTCCGTTCGGTTGGCAGAAGC-3') and Luc R (5'-CCAAAACCGTGATGGAATGGAACAACA-3') as described by Zhang et al., 2003.
Screening Cyp1a2-luc founders. For primary screening of each transgenic founder line, a group of three mice including both genders (one male and two females or two males and one female) were imaged for basal expression of the Cyp1a2-luc transgene. Lines were also tested for their response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at 100 µg/kg and 3-methylcholanthrene (3-MC) at 50 mg/kg. Mice were imaged daily for 3 days after injection. The criteria used for screening founding lines were: (1) high basal luciferase expression in liver and (2) upregulation of luciferase expression in liver by both TCDD and 3-MC injection. Five transgenic founding lines were screened, and one line was selected to fully characterize.
Chemicals. Dimethyl sulfoxide (DMSO), 3-methylcholanthrene (3-MC), phenobarbital (PB), benzo[a]pyrene (BP), and ß-naphthoflavone (BNF) were purchased from Sigma-Aldrich (St. Louis, MO). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was purchased from Cambridge Isotope Laboratories (Andover, MA).
Animal studies. Male and female Cyp1a2-luc transgenic mice at 812 weeks of age, in groups of three to five, were injected ip with a single dose of DMSO, TCDD dissolved in DMSO at 100 µg/kg, 3-MC suspended in DMSO at 50 mg/kg, saline, PB dissolved in saline at 100 mg/kg, corn oil, BP dissolved in corn oil at 10 mg/kg, BNF suspended in corn oil at 100 mg/kg. Mice were imaged as described below at T = 0 (pretreatment), 3, 6, 9, 24, 48, and 72 h after drug treatment.
In vivo imaging. In vivo bioluminescent imaging was performed as previously described (Contag et al., 1995). The substrate luciferin was injected into the intraperitoneal cavity at a dose of 150 mg/kg body weight (30 mg/ml luciferin) approximately 5 min prior to imaging. Mice were anesthetized with isoflurane/oxygen and placed on the imaging stage. Ventral and dorsal images were collected for 1 s using the IVIS® Imaging System 100 (Xenogen, Alameda, CA). Photons emitted from the liver region were quantified using LivingImage® software (Xenogen, Alameda, CA).
Ex vivo luciferase assay. Liver, duodenum, kidney, spleen, lung, heart, brain were homogenized and sonicated using a tissue disrupter (Sonic Dismembrator 60, Fisher Scientific, Pittsburgh, PA) in 800 µl of PBS buffer. Luciferase activity was determined over a 20-s integration time using the Luciferase Assay System and a TD 20/20 Luminometer (Promega, Madison, WI). Luciferase activity was normalized to relative light units (RLU) per mg of total protein in the homogenates. Protein content was measured using Bradford Reagent (Sigma-Aldrich, St. Louis, MO).
Effects of chemicals on the luciferase activity ex vivo. A female Cyp1a2-luc liver was homogenized in PBS solution. DMSO, TCDD at 100 µg/l, 3-MC at 50 mg/l, saline, PB at 100 mg/l, corn oil, BP at 10 mg/l, or BNF 100 mg/l was added to 100 µl of liver homogenate and the mixtures were incubated in room temperature for 15 min. Luciferase activity was determined as described above.
Northern Analysis
Tissue distribution of Cyp1a2 mRNA. Seven tissues including liver, duodenum, kidney, spleen, lung, heart, and brain from both male and female Cyp1a2-luc transgenic mice (three per group) were also analyzed by Northern blotting for tissue distribution. A C57BL/6 female mouse treated with TCDD at 100 µg/kg was used as a positive control. Total RNA was extracted using RNAWIZTM Reagent (Ambion, Inc., Austin, Texas). Fifteen µg of total RNA from each sample and 4µg of RNA from TCDD-treated animals were analyzed. A single-strand antisense full-length Cyp1a2 RNA probe was labeled using Strip-EZTM RNA StripAbleTM RNA Probe Synthesis and Removal Kit (Ambion, Inc., Austin, Texas). The blot was hybridized and detected following the instructions of the manufacturer using the BrightStar BioDetectTM Nonisotopic Detection Kit (Ambion, Inc., Austin, Texas).
Drug effects on the Cyp1a2 mRNA. Cyp1a2-luc transgenic female mice (two per group) were treated as described in the Animal Studies section. C57BL/6 female mice (two per group) treated with 100 µg /kg of TCDD and 50 mg/kg of 3-MC as positive controls. Mouse livers were removed and quickly frozen in liquid nitrogen 9 h after treatments. Fifteen µg of total RNA from each sample were analyzed using the Cyp1a2 probe. A blot with the sample loadings was hybridized with a ß-actin antisense RNA probe.
Western analysis. Liver samples from CD-1 and C57BL/6 male mice (3 mice per group) were homogenized and sonicated in cold PBS solution. Fifty µg of protein from each cytosolic fraction were separated on a 7% SDSpolyacrylamide gel and then transferred to a nitrocellulose membrane (Bio-Rad, CA). AhR protein was detected using primary rabbit polyclonal antisera against a human AhR peptide (Santa Cruz Biotechnology, Santa Cruz, CA) and peroxidase-conjugated secondary antibody goat-anti-rabbit IgG (Bio-Rad, Hercules, CA). Chemiluminescent detection reagents were purchased from Amersham Biosciences, Piscataway, NJ.
Cloning of AhR cDNA from CD-1 mouse mRNA. Total RNA was isolated from a pool of 20 female and 29 male CD-1 mouse liver samples using RNAWIZTM Reagent (Ambion, Inc., Austin, Texas). The mRNA was purified using the MicroPoly(A)PureTM Kit (Ambion, Inc., Austin, Texas). Since we had difficulties amplifying the entire AhR cDNA, we cloned the amino-terminal (N-terminal) portion (11254, start codon to BamHI site) and carboxyl-terminal (C-terminal) portion (12552547, BamHI site to stop codon) of the AhR cDNA separately. The AhR-TOP-HindIII primer 5'-CCCAAGCTTATGAGCAGCGGCGCCAACATCAC-CTATGCC-3' corresponding to nucleotides 130 and the AhR-R2 primer 5'-CCAACTCCCGCACTTGCTCACGGAGCCC-3' corresponding to nucleotides 1434 to 1461 were used to amplify the N-terminal region of AhR cDNA from the mRNA pool by reverse transcription polymerase chain reaction (RT-PCR) using ProSTARTM HF Single-Tube RT-PCR System (High Fidelity) Kit (Stratagene, La Jolla, CA). The HindIII/BamHI fragment from PCR product was cloned into the pGEM3Zf(+) vector (Promega, Madison, WI). The C-terminal region of the AhR cDNA was amplified using the AhR-F1 primer 5'-GGAGAGGCTGTGTTGTACGAGATCTCCAG-3' corresponding to nucleotides 12071235 and AhR-BOT-XmaI primer 5'-TCCCCCGGGCTACAGGAATCCACCAGGTGTGATATCGGG-3'. The BamHI/XmaI fragment from the PCR product was cloned into the pGEM3Zf(+)vector. Five N-terminal clones (N #1, N #5, N #8, N #10, and N #11) and six C-terminal clones (C #3, C #5, C#6, C#7, C#9, and C #11) were sequenced by the Stanford PAN Facility, Stanford, CA.
Statistical analysis. Data are presented in the text and figures as means ± standard error about the mean. Induction of the luciferase signal was analyzed by an analysis of variance with post hoc t-tests to evaluate the difference between luciferase activity at the 0 time point and each subsequent time point. In order to determine if there was an overall difference in response to drug compared with their solvents, a multivariate analysis of variance (MANOVA) model was used comparing the drug response for each drug with the response to vehicle. Female and male data were analyzed separately. Statistical tests were performed using the Statview statistical package (Version 5.0.1; SAS Institute, Cary, NC).
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RESULTS |
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In Vivo Drug Responses of the Cyp1a2-luc Reporter and the Endogenous Cyp1a2 Genes
We chose five different known mouse Cyp1a2 inducers to study the effects of drugs on transcriptional regulation of the Cyp1a2-luc reporter in vivo. Males and females in separate groups were challenged with 2,3,7,8-tetrachlorodibenzo-p-dioxin at 100 µg/kg, 3-methylcholanthrene at 50 mg/kg, phenobarbital at 100 mg /kg, benzo[a]pyrene at 10 mg/kg, and ß-naphthoflavone at 10 mg/kg body weight. DMSO, saline, and corn oil were used as vehicle controls for these drugs. Mice were imaged from the ventral side at 0 (before injection) and 3, 6, 9, 24, 48 and 72 h after a single administration of drug.
Injection of these drugs produced significant induction to various degrees of the Cyp1a2-luc transgene in vivo in both male (Fig. 2A) and female (Fig. 2B) mice, and both genders showed very similar response patterns. At the peak time and doses used, PB induced the Cyp1a2-luc reporter strongest with 10.9-fold induction in females and 6.4-fold induction in males, and TCDD increased the reporter signal moderately (7.1-fold in females; 3-fold in males). The 3-MC effect was marginal. The BP and BNF had no significant effect on the reporter signal. The PB effect appeared to be transient, with peak response between 6 and 9 h after injection, and signals returned to background completely at the 48-h time point. The TCDD effect was observed at 6 h after injection and was sustained for a longer period of time.
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DISCUSSION |
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It is very interesting that basal expression level of the Cyp1a2-luc was much higher in male mice than in female mice in multiple founding lines, while the endogenous Cyp1a2 mRNA showed no gender difference. Although previous studies have demonstrated that males have higher demethylation activity of caffeine by CYP1A2 protein than females in three of six inbred mouse strain (Casley et al., 1997), the CD-1 mouse Cyp1a2 mRNA level appeared to be independent of genders. It is possible that the Cyp1a2 promoter isolated form 129/SVJ genome confers the gender differences in the reporter expression. It has been reported that 17ß-estradiol suppresses the CYP1A expression in rainbow trout liver cells through the estrogen receptor (Navas and Segner, 2001
). In all five founding lines that were screened, there was a consistent gender difference, with the male mice having higher basal level of the transgene expression. Therefore, we believe that this gender difference is not due to effects of integration sites of the transgene.
The Cyp1a2-luc transgenic animal model that we have developed allows us to follow induction of the transgene in vivo over time using the IVIS® imaging system. Phenobarbital, a classic inducer of CYP1A, CYP2, and CYP3A genes, upregulated strongly the reporter in both genders, and the peak response was 69 h after a single dose of drug treatment. It has been reported that phenobarbital induces the mouse Cyp1a2 about 1.5- to 3-fold independent of AhR (Sakuma et al., 1999), which correlated well with our Northern result. It appears that phenobarbital highly activates the Cyp1a2-luc transgene, but stimulates only slight induction of the endogenous Cyp1a2 mRNA. This discrepancy could be due to the fact that the transgene was integrated into a genomic locus where a phenobarbital-responsive element(s) is nearby. It is also possible that phenobarbital-responsive elements exist in the promoter that was isolated from 129/SVJ mice. Females responded to phenobarbital treatment slightly more than males, which may be due to the lower basal background signals.
TCDD, 3-MC, BP, and BNF are prototypic aryl hydrocarbons that induce the Cyp1a1 and Cyp1a2 genes in mice through the classic AhR signaling pathway (Tukey and Nebert, 1984). However, we only observed about 3- and 7-fold induction by a very high dose of TCDD (100 µg/kg) in males and females, respectively, which is much less induction compared to the 20- to 30-fold induction at 10 µg/kg observed in a previous study in C57BL/6 mice (Okino et al., 1992
). Our Northern data clearly showed that the Cyp1a2 mRNA in CD-1 mice induced by TCDD and 3-MC was much less than that in C57BL/6. In the rats, other potent inducers like 3-MC, BP, and BNF that induced the CYP1A2 gene transcription about 50-fold (Pasco et al., 1993
) had no effect in the CD-1 Cyp1a2-luc reporter mice. It is clear that regulation of the CYP1A2 gene in rats is mainly transcriptional, as demonstrated by comparing Northern blotting and nuclear run-on analyses (Pasco et al., 1993
), rather than due to posttranscriptional accumulation of CYP1A2 mRNA proposed by Pasco et al. (1988)
and Silver and Krauter (1988)
. We could not detect BNF induction of the reporter transgene, but a good induction of the Cyp1a2 mRNA. This difference may be due to the observations that BNF is such a strong luciferase enzymatic inhibitor and that it negates the BNF induction of luciferase expression. Marginal induction by 3-MC may also be due to inhibition of the luciferase activity. Therefore, one should first determine if compounds have effects on the luciferase enzymatic activity before testing in vivo effects using the model.
It has been reported that genetic variations of AhR in mice lead to differences in regulation of Cyp1a genes in response to aromatic hydrocarbon inducers (Gonzalez et al., 1984; Nebert et al., 1975
, 1982
). The C57BL/6 strain is the prototypical Ah-responsive mouse, possessing a high-affinity receptor, while the DBA/2 strain is the prototypical Ah-nonresponsive mouse, with a low-affinity receptor. Polymorphic forms of mouse AhRs have been isolated from responsive C57BL/6 and nonresponsive DBA/2 and other mouse strains (Ema et al., 1992
, 1994
; Thomas et al., 2002
). TCDD, a potent Cyp1a inducer, induced Cyp1a1 and Cyp1a2 genes in both C57BL/6 and DBA/2, with a lower response in DBA/2 (Gonzalez et al., 1984
; Okey et al., 1989
). 3-MC had no effect on both Cyp1a1 and Cyp1a2 genes in the DBA/2 strain, while both genes were induced 15- to 20-fold in the C57BL/6 strain (Gonzalez et al., 1984
). 3-MC and BNF also induced rat CYP1A2 gene about 10-fold (Kawajiri et al., 1984
). Based on the relatively low induction of the Cyp1a2-luc transgene and the endogenous Cyp1a2 mRNA compared to C57BL/6 mice, we conclude that CD-1 strain is a poor Ah-responsive mouse strain, the first nonresponsive outbred mouse strain described. In another preliminary study, 30 mg/kg 3-MC induced the CYP1A1-luc transgene (human CYP1A1 promoter) about 313-fold in FVB female mice, an Ah-responsive strain, while 50 mg/kg 3-MC only induced the CYP1A1-luc about 103-fold in CD-1 female mice. These data further indicated that the CD-1 mice are less sensitive to Ah compounds.
To explain the low responsiveness in CD-1 mice, we speculated that there might be a similar mutation Ala375 to Val375 in the CD-1 AhR as in DBA/2 strain (Ema et al., 1994). However, sequence analyses of the CD-1 AhR cDNA demonstrated that the consensus sequences of polymorphic forms of the CD-1 AhR are identical to the responsive strains Balb/C and CBA/J with a normal Ala375. Point mutations found in CD-1 AhR individual clones may not play roles in determining the responsiveness, because most of these mutations have been found in other inbred strains, and no report shows that these positions are crucial for AhR function.
Since it has been reported that the low- or nonresponsive mouse strains express low levels of AhR protein (Bigelow and Nebert, 1986; Jana et al., 1998
), we compared the AhR levels between CD-1 and C57BL/6 mice by Western blot. No detectable 104-kD AhR protein in CD-1 mice suggests that the low responsiveness to Ah compounds may be due to the low expression of AhR protein. Although CD-1 livers also showed a little cross-reactivity at the 97-kD region, the intensity was much less than that in C57BL/6 livers, and therefore, that could just be nonspecific binding. Because the promoter for the reporter transgene was isolated for 129/SVJ mouse strain and this strain is an Ah-nonresponsive strain, this promoter region may have an imperfect AhR-responsive element(s) that leads to low induction. It also possible that additional responsive elements beyond the 8.4-kb promoter region are required for maximal induction of the Cyp1a2 gene. We cannot exclude possibilities that low responsiveness is due to mutations in other nuclear factors such as ARNT, HSP90, and AhR repressor. A point mutation in ARNT from mutant mouse Hepa-1c1c7 cells leads to low-affinity binding to xenobiotic response element (Numayama-Tsuruta et al., 1997
), and a polymorphism of human ARNT has also been reported (Scheel et al., 2002
). An AhR repressor protein was also identified which inhibits function of AhR (Mimura et al., 1999
). Recently, a humanized AhR knock-in mouse model demonstrated that humanized AhR mice responded to drugs in a fashion more similar to the nonresponsive DBA/2 strain rather than the C57BL/6 strain (Moriguchi et al., 2003
), suggesting the DBA/2 strain may be a better model to assess AhR-mediated toxic effects of compounds.
In summary, we have developed a Cyp1a2-luc transgenic reporter mouse model containing an 8.4-kb mouse Cyp1a2 promoter region driving a firefly luciferase cDNA in the CD-1 mouse background. Male mice expressed the Cyp1a2-luc transgene at higher levels than female mice. Phenobarbital and TCDD induced the reporter in liver, while the 3-MC effect was marginal. BP and BNF had no effect. These reporter mice responded to Ah compounds with sensitivity similar to DBA/2 and humanized AhR C57BL/6 mice (Moriguchi et al., 2003) and may predict human CYP1A2 responses in vivo.
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ACKNOWLEDGMENTS |
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NOTES |
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1 To whom correspondence should be addressed at Xenogen Corporation, 860 Atlantic Avenue, Alameda, CA 94501. Fax: (510) 291-6196. E-mail: wzhang{at}xenogen.com.
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