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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
Laboratory for Cellular and Biochemical Toxicology (S.M.-V., R.I.S., F.C.K.), Laboratory for Neurotoxicology (K.R.R.), Department of Pharmacology and Toxicology, and Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology (A.H.C.), Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey
Received for publication
October 13, 2005
Accepted
January 17, 2006.
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Abstract |
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-OH-E2, 6
-OH-E2, 14-OH-E2, 6-keto E1, and 2-OH-E1) and reduced the formation of the E2-17-oleoyl ester and the E2 3- and 17-glucuronides. In contrast, when given in combination with E2, PB increased the formation of both glucuronides. Cotreatment of animals with PB and E2 increased activities of NAD(P)H:quinone oxidoreductase and glutathione S-transferase to a greater extent than either compound alone. Collectively, these results show that the multiple actions of PB on hepatic metabolism of E2, including induction of E2 hydroxylation, glucuronidation, and antioxidant defense enzymes along with inhibition of E2 esterification in livers of female ACI rats, accompany a marked reduction of E2-dependent mammary tumors in this model.
). Treatment of rodents with PB induces the synthesis of hepatic microsomal enzymes that hydroxylate progesterone, estradiol (E2), estrone (E1), deoxycorticosterone, testosterone, 
4-androstene-3,17-dione, and cortisol (reviewed by Zhu and Conney, 1998). Endogenous estrogens are hydroxylated at multiple positions by several hepatic and nonhepatic microsomal monooxygenase systems (reviewed by Martucci and Fishman, 1993; Zhu and Conney, 1998). The alteration of microsomal hydroxylation of steroids by PB is reflected in vivo by enhanced metabolism and altered actions of steroids. For example, pretreatment of rats with PB decreases the uterotropic action of E2 and E1 and enhances their metabolism in vivo (Levin et al., 1967, 1968). Treatment of rats with PB also inhibits the growth-promoting effect of testosterone on the seminal vesicles (Levin et al., 1974) and decreases the anesthetic action of progesterone and deoxycorticosterone in rodents (Conney et al., 1966).
Oxidative stress arising from redox cycling of catechol estrogens formed during E2 metabolism has been suggested as an important factor in initiation and progression of many cancers, including mammary carcinogenesis (Cavalieri et al., 1997; Cavalieri and Rogers, 2004). In mammals, the liver contains high levels of cytochromes P450, which catalyze NAD(P)H-dependent oxidation of estrogens to various hydroxylated or keto metabolites (Martucci and Fishman, 1993; Zhu and Conney, 1998). Reaction of endogenous catechol estrogens with DNA causes formation of depurinating DNA adducts (Cavalieri et al., 1997; Cavalieri and Rogers, 2004; Li et al., 2004), which has been proposed to cause oncogenic mutations (Chakravarti et al., 1995). The carcinogenic effects of 4-catechol estrogens (E2 and E1) in the kidney of castrated male Syrian hamsters (Liehr et al., 1986) reinforce this hypothesis. However, administration of high doses of 2-OH-E2, 4-OH-E2, or 4-OH-E1 to ACI rats failed to cause mammary tumors under conditions in which E2 was highly active (Turan et al., 2004). In addition, the direct injection of estrone-3,4-quinone (the chemically reactive ortho-quinone derived from 4-OH-E1) under the nipples of the mammary glands in rats failed to cause mammary tumors, whereas injection of a positive control, a diol epoxide of benzo[c]phenanthrene, was highly active (el-Bayoumy et al., 1996).
In the present study, we investigated the effects of PB on the formation of mammary tumors induced by E2 in ACI rats, an estrogen-sensitive strain that is considered a unique model because of its high sensitivity to estrogen-dependent mammary ductal adenocarcinomas (80–100% incidence) within a relatively short time period (Shull et al., 1997; Harvell et al., 2000; Li et al., 2002). The main objective of the present study was to determine whether PB-induced increases in E2 metabolism in the liver corresponded with alterations in the formation of E2-induced mammary tumors. The liver is a major site of estrogen metabolism, and estrogen circulates primarily as inactive conjugates of E1 and E2 produced in the liver; i.e., conjugated E2 is a transport form of estrogen, which is converted back to active estrogen in target tissues such as mammary gland (reviewed in Zhu and Conney, 1998; Pasqualini 2004; Reed et al., 2005)
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Materials and Methods |
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-glucuronidase (EC 3.2.1.31
[EC]
), UDP-glucuronic acid (UDPGA), sodium phenobarbital, saccharic acid 1,4-lactone, p-nitrophenol, 1-chloro-2,4-dinitrobenzene (CDNB), reduced glutathione, cytochrome c, oleoyl coenzyme A, sodium azide, and Tris base were obtained from Sigma Chemical (St. Louis, MO). Glutathione reductase (140.7 U/mg protein) was purchased from Fluka Biochemica (Buchs, Switzerland), [35S]PAPS was purchased from New England Nuclear (Boston, MA), and PAPS (>99% pure) was purchased from H. Glatt and R. Landseidel, German Institute of Nutrition (Potsdam, Germany). [2,4,6,7,16,17-3H]Estradiol (s.a. 110–170 Ci/mmol) was purchased from NEN Life Science Products (Boston, MA). Pellets with or without E2 were purchased from Hormone Pellets Press (Shawnee Mission, KS). AIN-76A diet was purchased from Dyets Inc. (Bethlehem, PA). All other chemicals used were of the highest grade from standard sources.
Animals and Treatments
Female ACI rats (7–8 weeks old) were obtained from Harlan Sprague-Dawley Laboratory (Indianapolis, IN). The animals were housed individually in an Association for Assessment and Accreditation of Laboratory Animal Care International-accredited barrier facility under controlled temperature, humidity, and lighting conditions and were fed with AIN-76A diet (Dyets Inc.). Treatment protocols started 4 days after arrival of the animals. Rats received water ad libitum or 0.05% PB in their drinking water. A single 20-mg pellet containing 3 mg of E2 plus 17 mg of cholesterol was implanted subpannicularly in the shoulder region, as described previously (Li et al., 2002). Control animals were implanted with 20-mg cholesterol pellets alone. The rats were palpated for mammary tumors twice weekly and were weighed every 2 weeks for the duration of the experiment. Animals (n = 8–15) were killed by decapitation after 6, 12, or 28 weeks. The geometric volume of the tumors was determined using the formula: length x width x height x 0.5326, assuming a hemiellipsoid shape (Shah et al., 1999).
Serum Levels of E2. Trunk blood collected at decapitation was allowed to clot at 4°C for 6 h and centrifuged. The serum was collected and stored at –80°C. Circulating levels of E2 were determined in whole serum by radioimmunoassay, using Coat-A Count Estradiol RIA kits (Diagnostic Products, Los Angeles, CA). According to the manufacturer's instructions, this assay measures both bound and free E2 in serum.
Tissue Processing. All of the animals were subjected to macroscopic pathologic examination when killed, and the number, volume, and localization of mammary tumors were recorded. The mammary glands and the tumors were quickly removed. Portions of these tissues were fixed in Carnoy's solution for 4 h and processed for embedding in paraffin. Sections (6 µm) were prepared from each of the Carnoy's solution-fixed tissues and stained with hematoxylin and eosin. Selected estrogen target organs, including pituitary, adrenals, thymus, uterus, kidneys, and liver, were removed and weighed.
Preparation of Hepatic Subcellular Fractions. Liver cytosols and microsomes were prepared by differential centrifugation as described previously (Thomas et al., 1983) and stored at –80°C until used. The protein concentration was determined with the BCA protein assay kit (Pierce Chemical, Rockford, IL) according to the supplier's instructions using bovine serum albumin as a standard.
Enzyme Assays
NAD(P)H-dependent oxidation of E2 (cytochrome P450 assay) was carried out using liver microsomes incubated with 5 mM ascorbic acid, 3 mM magnesium chloride, 50 µM sodium phosphate buffer (pH 7.4), and 25 µM [3H]E2 (0.5 µCi) for 20 min at 37°C. The enzyme reaction was initiated with 2 mM NAD(P)H and terminated by the addition of 5 ml of ethyl acetate and vortexing. The ethyl acetate extracts were evaporated to dryness under nitrogen. The residue was dissolved in methanol and analyzed for metabolite composition by HPLC as described previously (Suchar et al., 1996; Mesia-Vela et al., 2002).
Fatty acyl-CoA:estradiol acyltransferase was assayed in reaction mixtures containing 50 µM [3H]E2 (1 µCi), 100 µM fatty acyl-CoA, and 5 mM magnesium chloride in 0.1 M sodium acetate buffer (pH 5.5) in a final volume of 0.5 ml. The reaction was initiated by the addition of liver microsomes (1 mg of protein/ml). After incubation at 37°C for 30 min, the reaction was arrested by placing the tubes on ice, followed by the addition of 0.2 ml of ice-cold sodium acetate buffer (pH 5.5) and extraction by vortexing with 4 ml of ethyl acetate (HPLC grade from Fisher Scientific, Pittsburgh, PA). Dry extracts were redissolved, and 90-µl aliquots were analyzed by HPLC as described previously (Xu et al., 2002). Metabolite quantification was based on the amount of radioactivity in the metabolite peak compared with the total radioactivity collected from the HPLC column from each sample.
Glucuronosyltransferase activity was assayed using a modification of a previously described method (Sanchez et al., 2003). The reaction mixture contained 1.0 mg of microsomal protein, 2 mM UDPGA, 5 mM MgC12, 100 µM [3H]E2 (0.15 µCi), and 50 mM Tris-HCl buffer, pH 8.5, in a final volume of 150 µl. The reaction was initiated by the addition of UDPGA. Incubations proceeded at 37°C for 15 min and were terminated by placing them on ice and adding 50 µl of ice-cold acetonitrile. The reaction mixtures were then vortexed and centrifuged at 3000g for 5 min, and 10 µl of the supernatants were used for the determination of E2 and E2 glucuronides by HPLC. The HPLC system consisted of a Shimadzu SCL-10A system controller with a Shimadzu SIL-10A autoinjector, two LC-10AD pumps, a SPD-10A UV-visible detector set at 280 nm, and an Eclipse XDB C18 (4.6 x 150 mm) column (MacMod Analytical, Chadds Ford, PA). The solvent system consisted of solvent A (0.1% acetic acid in water) and solvent B containing 20% methanol, 80% acetonitrile, and 0.1% acetic acid. E2 and its 3- and 17-hydroxyglucuronides were eluted with a 30-min linear gradient from 25 to 90% solvent B. Metabolite quantification was based on the amount of radioactivity in the metabolite peak compared with the total radioactivity collected from the HPLC column from each sample. The retention time of metabolites and E2 agreed with corresponding UV-absorbing peaks of standards. The glucuronides were identified by their coelution with authentic standards or by determination of E2 after hydrolysis in the presence of -glucuronidase (200 U/ml).
Cytosolic sulfotransferase (SULT) activity was determined using [35S]PAPS as cofactor. The incubations were carried out with 20 mM Tris·HCl, pH 7.5, 4 mM MgCl2, 10 µM [35S]PAPS (0.02 µCi), and 5 µM p-nitrophenol in 100 µl (Foldes and Meek, 1973).
Cytosolic NAD(P)H/quinone oxidoreductase (NQO1) was measured by reduction of cytochrome c (50 µM) in the presence of liver cytosol, 10 µM menadione, and 1 mM NAD(P)H. The reaction was monitored at 550 nm. The reactions were carried out in 100 mM potassium phosphate buffer, pH 7.7, containing 0.04% Triton X-100 at 25°C (Jaiswal et al., 1988). Activity of dicumarol-inhibitable menadione reductase was determined using an extinction coefficient of 21 mM/cm for cytochrome c.
Cytosolic glutathione S-transferase (GST) activity was measured in the presence of liver cytosolic protein, 1 mM CDNB, 1 mM reduced glutathione, and 100 mM potassium phosphate buffer, pH 6.5, at 25°C. Conjugation of CDNB with glutathione was monitored at 340 nm. Specific activity was calculated using an extinction coefficient of 9.6 mmol/cm (Habig et al., 1974).
Cytosolic glutathione peroxidase (GPx) activity was measured using hydrogen peroxide as the substrate and was monitored by the decrease in absorbance at 340 nm. Specific activity was calculated using an extinction coefficient for NAD(P)H of 6.22 mM/cm (Flohe and Gunzler, 1984).
Statistical Analysis of Data
Data are presented as the means ± S.E. Differences between means were assessed by ANOVA followed by the Bonferroni post hoc test, P < 0.05.
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Results |
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Effect of PB on the Incidence, Multiplicity, and Size of Mammary Tumors in E2-Treated ACI Rats
The first mammary tumor appeared during the 15th week in E2-treated rats. Fifty percent of the animals had mammary tumors by the 26th week, and 100% of the animals had mammary tumors by week 28. Although PB administration did not substantially alter the initial onset of E2-induced mammary tumors, it reduced to 53% the number of rats with mammary tumors at the end of the experiment (28 weeks) (Fig. 1). Treatment of the rats with PB had a dramatic inhibitory effect on the number and size of E2-induced mammary tumors observed at 28 weeks (96–97% inhibition) (Fig. 2).
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-hydroxy-E2, 6-hydroxy-E2, 14-hydroxy-E2, 4-hydroxy-E2, 6-keto-E2, and 2-hydroxy-E1 per liver (calculated from Tables 2 and 3). Because the latter compounds are relatively minor metabolites, the overall major effect of PB was to enhance the 2-hydroxylation of E2 as well as the 2-hydroxylation of E1.
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Effect of PB Administration on the Esterification of E2 by Fatty Acyl-CoA:E2-Acyltransferase in Liver Microsomes
Treatment of rats with E2 for 6 or 12 weeks had little or no effect on liver microsomal formation of E2-17-oleoyl ester compared with control rats (calculated from Tables 2 and 4); however, coadministration of PB and E2 reduced the esterification of E2 by fatty acyl-CoA:E2-acyltransferase significantly at both 6 and 12 weeks (Table 4). PB treatment alone decreased esterification of E2 only after 12 weeks of treatment.
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Effect of PB Administration on the Glucuronidation of E2 by Liver Microsomes
Treatment of rats with E2 for 6 or 12 weeks did not alter microsomal glucuronidation of E2 per milligram of Microsol protein at any experimental time; however, treatment with PB reduced the formation of both E2 glucuronides (3- and 17-) by 45 and 34%, respectively, at 12 weeks. When given in combination with E2, PB increased formation of both glucuronides by 1.2- to 1.5-fold/mg protein after 6 and 12 weeks, respectively (calculated from Tables 2 and 4).
Effect of E2 and PB Administration on Sulfotransferase and Antioxidant Enzymes in the Liver
Hepatic Sulfotransferase. E2 administration for 6 or 12 weeks decreased p-nitrophenol sulfonation per milligram of cytosolic protein by 
30% (Table 5). Administration of PB had little or no effect on p-nitrophenol sulfonation (SULT1A1) activity when given alone or together with E2 (Table 5).
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Antioxidant Enzymes. Although administration of PB caused a modest decrease in hepatic GPx activity per milligram of cytosolic protein and E2 treatment was inactive, the administration of E2 or PB for 6 or 12 weeks caused large increases in hepatic NQO1 and GST activity (Table 6). Administration of PB for 6 or 12 weeks caused a 3.7- to 4.2-fold increase in NQO1 activity per milligram of cytosolic protein, and administration of E2 alone increased this activity 2.6- to 3.7-fold (Table 6). Administration of PB for 6 and 12 weeks elevated GST activity 2.7- to 2.9-fold per milligram of cytosolic protein; and administration of E2 alone increased this activity 1.9- to 2-fold (Table 6).
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The administration of a combination of PB and E2 increased NQO1 activity 68 to 84% (4.9- to 6.3-fold) compared with the activity observed after administration of E2 alone. Administration of a combination of PB and E2 also increased GST activity beyond that seen with either compound alone (3.1- to 3.9-fold per mg of cytosolic protein) (Table 6). In summary, administration of E2 or PB alone caused large increases in the levels of the antioxidant enzymes, NQO1, and GST per milligram of cytosolic protein, and the effects of the combined administration of PB and E2 were even larger than those after administration of E2 or PB alone.
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Discussion |
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The inhibition of E2-dependent tumorigenesis by PB was accompanied by significant changes in both the oxidation of E2 and by smaller changes in conjugation reactions. In addition, PB treatment had a remarkable stimulatory effect on two antioxidant defense enzymes, NQO1 and GST, which may be particularly important for the protection of PB against mammary tumorigenesis in the ACI rat model. Because blood E2 levels were unchanged after PB, it is possible that E2 synthesis was enhanced to compensate for increased E2 metabolism. Further studies to clarify the relationship between alterations in hepatic metabolism of E2 and the profile of E2 metabolites in blood over the course of mammary tumor formation in the ACI rat model are clearly warranted.
Chemoprevention of E2-Induced Mammary Tumors and Modulation of Microsomal Oxidation of E2 by PB. The chemopreventive effect of PB probably involves multiple mechanisms including an increase in microsomal oxidation triggered by PB. The strong stimulatory effect of PB on the hepatic formation of E2-hydroxylated E2 metabolites including some that are formed only in trace amounts, if at all, in control animals (4-hydroxy-E2, 6-hydroxy-E2, 14-hydroxy-E2, 6-hydroxy-E2, and 6-keto-E1) is noteworthy. The formation and pattern of induction of hydroxylated metabolites of E2 by PB were similar to findings in other rat strains (Suchar et al., 1996), which differ from the ACI rat in sensitivity to E2-induced mammary tumors. The major hydroxylated metabolite produced in the liver of the ACI rat is 2-hydroxy-E2. This metabolite, which is potentially chemopreventive against mammary tumors, was markedly induced in liver microsomes by PB in rats also treated with E2. A number of studies indicated that the 2-methoxy derivative of this metabolite formed by catechol O-methyl transferase has strong antiproliferative and proapoptotic actions in a variety of human cancer cell lines, including human breast cancer lines in vitro (Lottering et al., 1992; Pribluda et al., 2000; Liu and Zhu, 2004). Furthermore, 2-methoxy-E2 has strong antiangiogenic and inhibitory effects on growth of mammary tumors in mice in vivo (Fotsis et al., 1994; Klauber et al., 1997). Recently, synergistic inhibitory effects of 2-methoxy-E2 and microtubule-disrupting agents were observed on the proliferation of human breast cancer cells (Han et al., 2005). Thus, the marked stimulatory effect of PB on the 2-hydroxylation of E2 may contribute to the inhibitory effect of PB on E2-induced mammary tumors in the ACI rat. The other hydroxylated metabolites, some of which (e.g., 4-hydroxy-E2) may be tumorigenic (Liehr 1997), were also increased to a variable extent by PB. Transport of some of these metabolites either in their free or conjugated form to mammary tissue may contribute to mammary tumorigenesis either by direct genomic effects or via oxidative stress in mammary tissue. It is unlikely that circulating 4-hydroxy-E2, 4-hydroxy-E1, or 16-hydroxy-E2 contributes to the carcinogenic effects of E2 in the ACI rat because these metabolites of E2 were not tumorigenic under conditions described above in which E2 caused mammary tumors (Turan et al., 2004). In addition, the direct injection of estrone-3,4-quinone (the chemically reactive ortho-quinone derived from 4-OH-E2) under the nipples of the mammary gland in CD rats failed to cause mammary tumors (el-Bayoumy et al., 1996). It is of interest that injection of 4-hydroxy-E2 or E2-3,4-quinone into the mammary gland of the female ACI rat resulted in 4-hydroxy-E2-1-N3-adenosine and 4-hydroxy-E2-1-N7-guanine adducts in DNA (Li et al., 2004). It will be of interest to determine whether these injections result in mammary cancer.
Chemoprevention of E2-Induced Mammary Tumors and Modulation of E2 Conjugation by PB. E2 3- and 17-glucuronidation, major inactivation pathways of E2, were modestly increased when PB was coadministered with E2. In contrast, glucuronidation of E2 was reduced by PB treatment alone at 12 weeks. Reduction in the capacity of liver to form E2 glucuronides after chronic exposure to PB may increase amounts of active E2 available for transport to E2 target tissues such as mammary tissue. However, when PB was given concomitantly with E2, the formation of E2 3- and 17-glucuronide was modestly increased, suggesting enhanced inactivation of E2 in these animals. Reduction of microsomal fatty acyl-CoA:E2 acyltransferase activity in PB-treated rats would reduce the formation of fatty acyl esters of E2, which are postulated to be long-term storage forms of E2 in fatty tissues such as the breast (Xu et al., 2002). Furthermore, hepatic cytosolic sulfotransferase (SULT1A1), which may be involved in the conversion of E2 to conjugates that serve as transport and storage forms, was also decreased slightly by treatment with combinations of PB and E2.
Chemoprevention of E2-Induced Mammary Tumors and Modulation of Antioxidant Pathways by PB and E2. The observation that administration of PB alone or together with E2 strongly induced the activity of NQO1 and GST in liver after 6 and 12 weeks of treatment is intriguing because these activities may be linked to detoxification of reactive oxygen species generated by redox cycling of E2 catechols, and increased levels of these antioxidant enzymes have been associated with anticarcinogenic effects (Ramos-Gomez et al., 2001). It is very important to determine whether the actions of PB observed in liver also occur in mammary tissue. The effects of PB on NQO1 and GST in liver were opposite to those on GPx and were in accord with the idea that regulation of expression of GPx differs from that of NQO1 and GST (Radjendirane et al., 1998; Esposito et al., 2000). It is also of considerable interest that administration of E2 alone increases the level of antioxidant enzymes, a finding observed earlier by our group (Sanchez et al., 2003; Mesia-Vela et al., 2004). Moreover, the induction of NQO1 and GST in response to chronic treatment with E2 seems to be specific for the ACI rat (Sanchez et al., 2003). The stimulatory effect of PB administration alone or together with E2 on NQO1 and GST activity suggests that PB induction of antioxidant enzymes may play a role in the protective effect of PB on E2-induced breast cancer.
In conclusion, the growth and multiplicity of E2-dependent mammary tumors in the ACI rat is markedly reduced by PB in the drinking water. This reduction of mammary tumors in the ACI rat is accompanied by multiple effects of PB on hepatic metabolism, including induction of E2 hydroxylation via NAD(P)H-dependent oxidations (predominantly an increase in 2-hydroxy-E2 formation), by an alteration in the formation of E2 conjugates, and by the induction of important antioxidant defense activities. Such changes induced by PB may reduce the incidence of mammary tumors by 1) enhancing the formation of a metabolite (2-methoxy-E2) that is inhibitory to mammary tumor growth, 2) decreasing the formation of fatty acid esters of E2 metabolites that serve as long-term depot forms of hormone in mammary tissue, 3) maintaining the formation E2 glucuronidation in animals treated chronically with the hormone, and 4) elevation of antioxidant defense enzymes. Thus, PB-induced alterations in hepatic E2 metabolism leading to the inactivation of E2 and to the increased activity of antioxidant enzymes need to be considered as determinants for E2-dependent mammary tumor formation in the ACI rat model.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: PB, phenobarbital; ACI, August-Copenhagen Irish; E2, estradiol; E1, estrone; UDPGA, UDP-glucuronic acid; CDNB, 1-chloro-2,4-dinitrobenzene; PAPS, 3-phosphoadenosine 5'-phosphosulfate; HPLC, high-performance liquid chromatography; SULT, cytosolic sulfotransferase; NQO1, NAD(P)H:quinone oxidoreductase; GST, glutathione S-transferase; GPx, glutathione peroxidase; ANOVA, analysis of variance.
Address correspondence to: Dr. Frederick C. Kauffman, Rutgers University, 41 Gordon Rd., Piscataway, NJ 08854. E-mail: kauffma{at}rci.rutgers.edu
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