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[Cancer Research 63, 6532-6536, October 1, 2003]
© 2003 American Association for Cancer Research

Endocrinology

Human Cytochrome P450 3A7 Has a Distinct High Catalytic Activity for the 16{alpha}-Hydroxylation of Estrone but not 17ß-Estradiol1

Anthony J. Lee, Allan H. Conney2 and Bao Ting Zhu3

Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208 [A. J. L., B. T. Z.], and Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, College of Pharmacy, Rutgers–The State University of New Jersey, Piscataway, New Jersey 08854 [A. H. C.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Like catechol estrogens, 16{alpha}-hydroxylated estrogens are hormonally active, chemically reactive, and potentially mutagenic. We report here our novel findings that human CYP3A7 has a distinct high catalytic activity for the NADPH-dependent 16{alpha}-hydroxylation of estrone (E1; at 10 nM to 200 µM substrate concentrations) but not for the 16{alpha}-hydroxylation of 17ß-estradiol (E2). At a physiologically relevant low substrate concentration (10 nM), CYP3A7 had a strong catalytic activity for the 16{alpha}-hydroxylation of E1, and the ratio of its 16{alpha}-hydroxylation to 2-hydroxylation was 107%. In addition to 16{alpha}-hydroxylation, CYP3A7 also had catalytic activity for the 2-, 4-, 6ß-, and 16ß-hydroxylation of E1. However, when E2 was the substrate, CYP3A7 had only very weak catalytic activity for its 16{alpha}-hydroxylation (<6% of E1 16{alpha}-hydroxylation), and the ratio of its 16{alpha}-hydroxylation to 2-hydroxylation was 10–33%. Enzyme kinetic analysis showed that the maximal velocity and substrate-binding affinity (1/Km) for CYP3A7-mediated 16{alpha}-hydroxylation of E1 were both ~10 times higher than those for E2, thereby giving the maximal velocity:Km ratio of >100 times higher for the 16{alpha}-hydroxylation of E1 than for E2. Given the recent findings that human CYP3A7 is a polymorphic isoform also expressed in adult liver and certain extrahepatic tissues (in addition to fetal tissues), our data raise the possibility that CYP3A7 may be an important catalyst for the local and/or systemic formation of the procarcinogenic 16{alpha}-hydroxyestrone in women.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Catechol estrogens (4-OH-E24 in particular) and 16{alpha}-hydroxylated estrogens are two well-known groups of endogenous estrogen metabolites that have strong hormonal activity, high chemical reactivity, and also potential genotoxicity/mutagenicity (1, 2, 3, 4, 5) . Because of their unique biological and chemical properties, these two groups of estrogen metabolites have been suggested to play an important role in the etiology of estrogen-induced cancers (2 , 6) . In the past decade or so, one of the notable efforts in this area of research is to identify hepatic and extrahepatic human CYP isoforms that have distinct catalytic activity for the formation of these bioactive estrogen metabolites. Whereas several human hepatic or extrahepatic CYP isoforms (such as CYP1A1, 1A2, and 3A4) were found to have dominant 2-hydroxylase activity, human CYP1B1 (an extrahepatic isoform) and CYP3A5 (mainly a hepatic isoform) were found to have distinct catalytic activity for the formation of 4-OH-E2 and 4-OH-E1 (7 , 8) . In comparison, much less is known about the catalytic activity of various human CYP isoforms for the 16{alpha}-hydroxylation of E2 and E1. It is of interest to note that it has been a long-held view that 16{alpha}-hydroxylation of estrogens in humans would only occur with E1 as substrate but not with E2 (9) . However, when the 16{alpha}-hydroxylation of E1 and E2 was analyzed recently with 33 adult human liver microsomes (8 , 10) , we found that the average rates for their 16{alpha}-hydroxylation were very low, and no marked differences were observed between these two estrogen substrates for most of the liver microsomal preparations assayed. There is currently no published information available on possible CYP isoform(s) with selective catalytic activity for the 16{alpha}-hydroxylation of E1 or E2. We report here a novel finding that human CYP3A7 has a distinct high catalytic activity for the NAPDH-dependent 16{alpha}-hydroxylation of E1 but not of E2. The catalytic activity of CYP3A7 for estrogen 16{alpha}-hydroxylation was compared with that of 14 other human CYP isoforms.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Chemical Reagents and Human CYP Isoforms.
E1, E2, 16{alpha}-OH-E2, NADPH, and ascorbic acid were purchased from the Sigma Chemical Co. (St. Louis, MO). 16ß-OH-E1 was biosynthetically prepared in our laboratory from 16ß-OH-E2 through incubations with human liver microsomes in the presence of NAD+ as cofactor. The product was extracted with ethyl acetate and then separated by the HPLC (described later). The reference compounds for all of the other estrogen metabolites used in the present study were obtained from Steraloids, Inc. (Newport, RI). N,O-bis(trimethylsilyl)trifluoroacetamide containing 1% trimethylchlorosilane was obtained from Pierce Chemical Co. (Rockford, IL). [2,4,6,7,16,17-3H]E2 and [2,4,6,7-3H]E1 (numerically labeled, specific radioactivity of 110 and 65.5 Ci/mmol, respectively) were purchased from Perkin-Elmer Life Sciences (Boston, MA).

Fifteen selectively expressed human CYP isoforms were obtained from BD Gentest Co. (Woburn, MA). These human CYP isoforms were expressed in insect cells that were selectively transfected with a baculovirus expression system containing the cDNA for each of the desired human CYP isoforms.

Assay of the NADPH-dependent Metabolism of [3H]]E2 or [3H]]E1 by Human CYP Isoforms.
It is of note that all of the glass test tubes used in the present study were silanized with 5% (v/v) dimethyldichlorosilane to reduce physical adsorption of hydroxylated estrogen metabolites to the test tubes. The reaction mixture for the in vitro metabolism of estrogens consisted of microsomes (at 70 pmol of CYP/ml), a desired concentration of [3H]E1 or [3H]E2, 2 mM NADPH, and 5 mM ascorbic acid in a final volume of 0.5 ml of a buffer solution (pH 7.4). The presence of 5 mM ascorbic acid in the incubation mixture has been shown previously to protect catechol estrogen metabolites from oxidative degradation without significantly altering the enzyme activity. The enzymatic reaction was initiated by addition of microsomes, and the incubations were carried out at 37°C for 20 min with mild shaking. The microsomal reaction was arrested by placing test tubes on ice and then immediately extracted with 4 ml of ethyl acetate. The organic supernatants were transferred to another set of test tubes and dried under a stream of nitrogen. The resulting residues were redissolved in 60 µl of methanol, and an aliquot (50 µl) was injected into the HPLC for analysis of estrogen metabolite composition with in-line UV and radioactivity detections as described earlier (8 , 10) . The calculation of the amount of each estrogen metabolite formed was based on the amount of radioactivity detected for each corresponding metabolite peak. Here it should also be noted that CYP isoform-mediated formation of hydroxylated or keto metabolites of [3H]E2 or [3H]E1 at any of their [3H]-labeled positions (namely, 2, 4, 6, 7, 16, and 17 for [3H]E2 and 2, 4, 6, and 7 for [3H]E1) was known to remove tritium from the substrate, resulting in the formation of [3H]H2O. Therefore, in the present study the calculated final rates for the formation of hydroxylated metabolites at the [3H]-labeled positions were adjusted according to the estimated loss of radioactivity in each of these products.

Structural Identification of E2 or E1 Metabolites.
The identity of E2 or E1 metabolites formed by CYP3A4 was confirmed through comparisons of their HPLC retention times, GC/MS retention times, and mass fragmentation spectra with all of the authentic reference compounds. For the purpose of comparison, the mass spectrum for each trimethylsilylated reference compound was obtained using our GC/MS system under the same analytical conditions for metabolically formed estrogen metabolites. The method for the GC/MS analysis of estrogen metabolites was described in our recent studies (8 , 10) .


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
We compared the catalytic activity for the 16{alpha}-hydroxylation of E1 and E2 by 15 human CYP isozymes from several families. The rates of their 16{alpha}-hydroxylation (at a representative 20 µM substrate concentration) and the ratios of their 16{alpha}-hydroxylation to 2-hydroxylation were summarized in Table 1Citation . Among all of the 15 CYP isoforms analyzed, CYP1A1, 2C8, 3A4, and 3A5 showed a detectable catalytic activity for the 16{alpha}-hydroxylation of E1 and E2. In general, E1 was somewhat more prone to be hydroxylated at the 16{alpha}-position by these CYP isoforms than was E2. Surprisingly, CYP3A7 had a distinct high catalytic activity for the 16{alpha}-hydroxylation of E1, but its catalytic activity for the 16{alpha}-hydroxylation of E2 was very low, <10% of its activity for E1.


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  		Table 1 The rate of estrogen 16{alpha}-hydroxylation and the ratio of estrogen 16{alpha}-hydroxylation: 2-hydroxylation by 15 selectively expressed human CYP isoforms

The CYP enzymes were selectively expressed in insect cells infected with a Baculovirus expression system containing the desired cDNA (purchased from BD Gentest). The incubation mixture consisted of 20 µM of [3H]E1 or [3H]E2, 70 or 140 pmol of P450/ml, 2 mM NADPH and 5 mM ascorbic acid in a final volume of 0.5 ml of the reaction buffer. The incubation was at 37°C for 20 min with mild shaking. The rate of 16{alpha}-hydroxylation was expressed as average ± SD from triplicated determination. The method for the HPLC separation of the estrogen metabolites was described in "Materials and Methods."

 
With this interesting initial observation, we then further characterized the profiles of various estrogen metabolites formed by human CYP3A7 using many E1 and E2 substrate concentrations (from 10 nM to 200 µM), with a focus on the formation of 16{alpha}-hydroxylated metabolites. At physiologically relevant low concentrations (such as 10 nM) of E1, 16{alpha}-OH-E1 became the major metabolite formed by CYP3A7, which accounted for 30–50% of the total activity for the oxidative metabolism of E1. The ratio of E1 16{alpha}-hydroxylation:2-hydroxylation was 107% at a 10 nM substrate concentration, and the ratio was decreased to 65% when E1 substrate concentration was increased to 25 µM. Representative HPLC metabolite traces at different E1 substrate concentrations were shown in Fig. 1Citation .



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  		Fig. 1. Representative HPLC traces for the NADPH-dependent metabolism of different concentrations of [3H]E1 by human CYP3A7. CYP3A7 was selectively expressed in insect cells infected with a Baculovirus expression system containing the desired cDNA (purchased from BD Gentest). The incubation mixture consisted of 20 µM of [3H]E1 or [3H]E2, 70 pmol of P450/ml, 2 mM NADPH, and 5 mM ascorbic acid in a final volume of 0.5 ml of the reaction buffer. The incubation was at 37°C for 20 min with mild shaking. The method for the HPLC separation of the estrogen metabolites was described in "Materials and Methods." The catalytic activity and cytochrome b5 content of the CYP3A7 microsomes were 2.5 pmol of 6ß-hydroxytestosterone formed/pmol of CYP/min and 220 pmol/mg of protein, respectively.

 
In addition to the formation of 16{alpha}-OH-E1, CYP3A7 also catalyzed the conversion of E1 to 2-OH-E1 plus a small amount of 4-OH-E1 (Fig. 1)Citation . 2-OH-E1 was formed in comparable amounts as 16{alpha}-OH-E1 at low E1 substrate concentrations, but its formation was slightly more than 16{alpha}-OH-E1 at higher E1 concentrations (Fig. 1)Citation . To confirm the structural identities of the major metabolite peaks (namely, 16{alpha}-OH-E1, 2-OH-E1, and 4-OH-E1), we collected the eluents of these peaks from the HPLC, and then subjected them to GC/MS analyses. Notably, very small amounts of 6ß-OH-E1 and 16ß-OH-E1 (which were coeluted with 16{alpha}-OH-E1 on the HPLC) were also found to be formed by CYP3A7 when E1 was the substrate. On the basis of selective monitoring of the most abundant ions (m/z) for these metabolites (namely, m/z 286 for 16{alpha}- and 16ß-OH-E1; m/z 340 for 6ß-OH-E1), we found that the ratios among 6ß-OH-E1, 16{alpha}-OH-E1, and 16ß-OH-E1 were ~2:92:6 at 5 and 50 µM E1 concentrations (data not shown).

In comparison, when E2 was the substrate, 2-OH-E2 was the major metabolite, and smaller amounts of 4-OH-E2 and 6ß-OH-E2 were also formed by CYP3A7. 16{alpha}-Hydroxylation was only a very minor metabolic pathway, with the ratio of its 16{alpha}-hydroxylation:2-hydroxylation ~10% (Fig. 2)Citation . The overall catalytic activity of CYP3A7 for the oxidative metabolism of E2 was lower than its activity for the metabolism of E1, and the rate of E2 16{alpha}-hydroxylation was <6% of the rate of E1 16{alpha}-hydroxylation.



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  		Fig. 2. Representative HPLC traces for the NADPH-dependent metabolism of [3H]E2 by human CYP3A7. The experimental procedures were the same as described in the legend to Fig. 1Citation .

 
We also estimated the kinetic parameters (KM and Vmax) for CYP3A7-mediated 16{alpha}-hydroxylation of E1 and E2, as well as for the CYP3A7-mediated 2- and 4-hydroxylation. As shown in Fig. 3Citation , the CYP3A7-mediated formation of each of these estrogen metabolites followed the typical Michaelis-Menten’s curve patterns. CYP3A7 had a high capacity (Vmax = 1423 pmol/nmol of CYP/min) and a relatively high affinity (1/KM = 0.1 µM-1) for the 16{alpha}-hydroxylation of E1. In comparison, the Vmax for E2 16{alpha}-hydroxylation was ~1/10 of the Vmax for E1 16{alpha}-hydroxylation, and the KM for E2 was ~10 times higher than that for E1 (Fig. 3)Citation . Accordingly, the Vmax:KM ratio of CYP3A7-mediated 16{alpha}-hydroxylation of E1 was >100-fold higher than that for the 16{alpha}-hydroxylation of E2.



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  		Fig. 3. Michaelis-Menten curves (top panels), Eadie-Hofstee plots (middle panels), and the calculated kinetic parameters (bottom panels) for the 2-, 4-, and 16{alpha}-hydroxylation of E1 (left panels) or of E2 (right panels) by human CYP3A7. The experimental procedures were the same as described in the legend to Fig. 1Citation . The KM and Vmax values were obtained by nonlinear regression using Prism software (GraphPad Software, Inc., San Diego, CA).

 
Lastly, it is of note that copresence of higher levels of cytochrome b5 (such as in the case of CYP3A4 versus CYP3A4 + b5) nonselectively enhanced the overall catalytic activity of the CYP isoform toward the formation of various estrogen metabolites (data not shown). This activation likely is because of a nonspecific mechanism, such as the increased availability of the second electron that is required for the CYP-mediated reactions.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of our present study showed that among the 15 selectively expressed human CYP isoforms assayed, only CYP1A1, 2C8, 3A4, 3A5, and 3A7 showed detectable catalytic activity for the 16{alpha}-hydroxylation of E1 and E2. We report here, for the first time, that CYP3A7 had a distinct high catalytic activity for the 16{alpha}-hydroxylation of E1 but not of E2 (Table 1)Citation . Enzyme kinetic analysis showed that the Vmax and substrate-binding affinity (1/KM) for CYP3A7-mediated 16{alpha}-hydroxylation of E1 were both ~10 times higher than those for E2, thereby giving a Vmax:KM ratio >100 times higher for the 16{alpha}-hydroxylation of E1 than for E2.

The differential rates of the 16{alpha}-hydroxylation of E1 versus E2 likely are determined by their different structures at the C17-position. We believe that the presence of a C17-keto group in the steroid is essential for it to be a suitable substrate for the 16{alpha}-hydroxylation by CYP3A7. In support of this suggestion, earlier studies have reported that whereas CYP3A7 was capable of catalyzing the 16{alpha}-hydroxylation of dehydroepiandrosterone and its 3-sulfate (both have a C17-keto group), it could not catalyze the 16{alpha}-hydroxylation of testosterone or cortisol (both lack a C17-keto group; Refs. 11 , 12 ).

It is of great interest to point out that the long-held view that 16{alpha}-hydroxylation only occurred with E1 as the substrate (9) appears to be true in the case of CYP3A7 as a catalyst. Notably, although CYP3A7 was originally found in human fetal liver where it accounted for 30–50% of total CYP contents (13 , 14) , studies have also suggested that CYP3A7 is expressed in human uterine endometrium, placenta, adrenal gland, and prostate (15 , 16) . In addition, the presence of constitutive or induced expression of CYP3A7 in adult human liver has also been suggested (17 , 18) , and its expression in adult liver and intestine appears to have a polymorphic distribution, with an estimated ~10% of Caucasians belonging to a distinct subgroup of high expression phenotype (19) . In light of this information, the findings of our present study raise the possibility that human CYP3A7 may be an important catalyst for the local and/or systemic formation of 16{alpha}-OH-E1 in humans. It is important to note that when the 16{alpha}-hydroxylation of E1 or E2 was recently analyzed with 33 adult human liver microsomes (8 , 10) , the average rates for the 16{alpha}-hydroxylation of these two estrogens were found to be similarly low for most of the liver microsomal preparations. This observation indicates that the contribution of CYP3A7 to hepatic estrogen 16{alpha}-hydroxylation in most adult human liver samples likely is rather minimal.

It is well known that very large amounts of 16{alpha}-OH-E2 (estriol) are present in blood and urine of pregnant women. It has been suggested that dehydroepiandrosterone sulfate (synthesized in the fetal adrenal glands) is metabolically converted to 16{alpha}-hydroxydehydroepiandrosterone sulfate in the adrenal glands and liver, which is then further aromatized to form 16{alpha}-OH-E2 in the placenta. It is believed that the fetus is the source of ~90% of the precursor for 16{alpha}-OH-E2, because of the presence of high levels of CYP3A7 in fetal tissues. However, on the basis of the findings of our present study, it appears that the CYP3A7-mediated 16{alpha}-hydroxylation of E1 in the fetal liver, coupled with C17-reduction by 17ß-hydroxysteroid dehydrogenase, could be another potential pathway for the formation of 16{alpha}-OH-E1 and 16{alpha}-OH-E2 in a pregnant woman.

In summary, human CYP3A7 has a distinct high catalytic activity for the NAPDH-dependent 16{alpha}-hydroxylation of E1, but not of E2. Additional studies are warranted to determine whether the CYP3A7 expression levels correlate with the tissue or circulating levels of 16{alpha}-OH-E1 and also with the risk of human breast or endometrial cancer.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by Grant CA74787 from the NIH. Back

2 William M. and Myrle W. Garbe Professor of Cancer and Leukemia Research. Back

3 To whom requests for reprints should be addressed, at Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Room 617 of Coker Life Sciences Building, 700 Sumter Street, Columbia, SC 29208. Phone: (803) 777-4802; Fax: (803) 777-8356; E-mail: BTZhu{at}cop.sc.edu Back

4 The abbreviations used are: E2, 17ß-estradiol; E1, estrone; OH, hydroxy; CYP, cytochrome P450; HPLC, high performance liquid chromatography; GC/MS, gas chromatography/mass spectrometry. Back

Received 4/16/03. Revised 7/22/03. Accepted 7/22/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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