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,2
Departments of
* Nutrition and Health Sciences, and
Animal Science, and Biochemistry, University of Nebraska at Lincoln, Lincoln, NE
2To whom correspondence should be addressed. E-mail: jzempleni2{at}unl.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • biotin • cytochrome P450 1B1 • DNA breaks • human • Jurkat cells
In mammals, biotin serves as a coenzyme for acetyl-CoA carboxylase, pyruvate carboxylase, propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (1). These enzymes catalyze essential steps in the metabolism of glucose, amino acids, and fatty acids (1). Histones (DNA-binding proteins) also contain covalently bound biotin (2–4); biotinylation of histones might play a role in the cellular response to DNA damage (5,6).
Biotin supply affects the expression of a large number of mammalian genes (7–18). In a recent DNA microarray study we identified 139 and 131 genes that were upregulated and downregulated, respectively, in lymphocytes from healthy adults in response to supplementation with biotin (19). In that study, cytochrome P450 1B1 (CYP1B1)3 ranked fourth among the genes that were upregulated by biotin supplementation: the abundance of CYP1B1 mRNA was 164% greater after supplementation than before supplementation (19). Some of the effects of biotin on transcriptional activities of genes are mediated by two members of the Sp/KLF family of transcription factors, i.e., Sp1 and Sp3 (20). The 5'-flanking region of the human CYP1B1 gene contains 11 putative binding sites for Sp1 and Sp3 (denoted "Sp1 sites") that are important for transcriptional activation (21–23). Theoretically, Sp1 or Sp3 might mediate effects of biotin on the expression of CYP1B1.
Currently, the cytochrome P450 superfamily of genes consists of 50 genes (including CYP1B1) and 58 pseudogenes (24). The effects of biotin on the expression of CYP1B1 are likely to be physiologically important, based on the following lines of evidence. Cytochromes P450 hydroxylate xenobiotics and estrogens ("metabolic activation"), creating electrophilic mutagens (25). For example, CYP1B1 activates polycyclic aromatic hydrocarbons and aryl amines (26), enhancing the susceptibility for lymphomas (27). Similarly, CYP1B1 hydroxylates the endogenous metabolite 17ß-estradiol (28); 4-hydroxylated estradiol causes single-stranded breaks in DNA and 8-hydroxylation of guanine bases in DNA (29,30). Metabolic activation of carcinogens and estrogens is a key factor in carcinogenesis of the human prostate (31,32), breast (29), and uterus (33). CYP1B1 is expressed in most peripheral tissues and in malignant tumors (26,34,35).
In this study, we tested the hypotheses that Sp1 sites in the CYP1B1 gene mediate transcriptional activation by biotin in a human T cell line (Jurkat cells); that biotin supplementation is associated with increased abundance and activity of CYP1B1; and that increased abundance of CYP1B1 in biotin-supplemented cells is associated with increased occurrence of single-stranded DNA breaks compared with biotin-deficient cells.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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In some cases, cells were treated as follows: 1) 0.7 nmol/L of 17ß-estradiol for 24 h to provide substrate for metabolic activation by CYP1B1 (28); 2) 15 nmol/L of (E)-1-(2,4-dimethoxyphenyl)-2-(3,5-dimethoxyphenyl)-ethene for 24 h to inhibit CYP1B1 (40); this compound was generously provided by Sanghee Kim (Seoul National University, South Korea); 3) 10 mmol/L of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 24 h to induce expression of CYP1B1 (34); and 4) 88 µmol/L of zeocin for 1 h to induce single-stranded DNA breaks (41).
Biotin-dependent carboxylases. Biotin-dependent carboxylases are good markers for cellular biotin (1). Biotinylated carboxylases in cell extracts were resolved by polyacrylamide gel electrophoresis and probed using streptavidin peroxidase (15). Densitometric analysis of gels was conducted as described (20). Activities of propionyl-CoA carboxylase were quantified in cell lysates as described (15).
Reporter-gene constructs. The following reporter-gene constructs were used to quantify effects of biotin on the transcriptional activity of the CYP1B1 gene: 1) a construct of the luciferase reporter gene driven by the 5'-flanking region of the human CYP1B1 gene (bp –1523 to + 20 from the transcription initiation site) was provided by Simon D. Spivack (Wadsworth Center, NYS Department of Health, Albany, NY); this plasmid has been denoted "1B1-WT" (42); 2) a construct of the luciferase reporter gene driven by the 5'-flanking region of the murine CYP1B1 gene (bp –1075 to + 371 from the major transcription start site) was provided by Colin R. Jefcoate (Medical Science Center, University of Wisconsin, Madison, WI); this plasmid has been denoted "p1075/+371" (43); 3) a promoter-free plasmid containing the luciferase gene (denoted "pGL3-Basic") was purchased from Promega; and 4) a construct of the ß-galactosidase reporter gene driven by the RSV promoter (denoted "RSV ßgal") was provided by Brett R. White (University of Nebraska-Lincoln).
Transfections and reporter-gene analyses were conducted as described (17). Reporter-gene activities were quantified 48 h after transfection. Luciferase activities were normalized for transfection efficiency using ß-galactosidase activities. Data are expressed as ratios of luciferase activities in cells transfected with 1B1-WT or p1075/+371 to activities in cells transfected with pGL3-Basic.
Northern blots. Expression of CYP1B1 and histone H4 (control) was quantified by Northern blot analysis. Gene-specific probes for Northern blots were generated by PCR as described (44), using the following primers: 5'-AAA GTA CAA CTA ACG CAA CC-3' and 5'-CCA ACT CTT GTC ACC TCG TA-3' for human CYP1B1 (GenBank accession number U03688); and 5'-ATG TCT GGT AGA GGC AAA GGT GGT AAA-3' and 5'-TCA GCC ACC AAA GCC GTA CAG AGT GCG-3' for histone H4 (GenBank accession number M60749). The identity of the probes was confirmed by sequencing in the Genomic Research Core Facility at the University of Nebraska-Lincoln (data not shown). Radiolabeling of probes and Northern blot analyses were conducted as described (44). The abundance of mRNA was quantified by gel densitometry (44); the abundance of CYP1B1 mRNA was normalized by the abundance of histone H4 mRNA.
Electrophoretic mobility shift assays (EMSAs). The 5'-flanking region of the CYP1B1 gene contains the following binding sites for transcription factors. 1) Sp1 sites (GC boxes, CACCC boxes): various members of the Sp/KLF family of transcription factors (including Sp1 and Sp3) have affinity for Sp1 sites (45). Binding of transcription factors to Sp1 sites may cause transcriptional activation or repression, depending on the context (46). The nuclear abundance of Sp1 and Sp3 correlates with biotin supply in human cells (20). 2) Xenobiotic responsive elements (XREs): environmental toxicants such as TCDD bind and activate a receptor designated the aryl hydrocarbon receptor (AhR); ligand-bound AhR forms a heterodimer with the AhR nuclear translocator (ARNT) (23). Binding of the AhR/ARNT dimer to XREs enhances transcriptional activity of the CYP1B1 gene (21,23). The regulatory region of the human CYP1B1 gene contains 8 XREs (23).
EMSAs were used to identify transcription factors and response elements that mediate effects of biotin on the transcriptional activity of CYP1B1. EMSAs were conducted using nuclear extracts and double-stranded oligonucleotide probes as described (20); the abundance of the transcription factor Oct-1 does not depend on biotin and was quantified as a control (20). The following probes were used for the EMSAs (complementary strands not shown): Sp1 consensus site = 5'-ATT CGA TCG GGG CGG GGC GAG C-3'; XRE 2 = 5'-GCT CCG CAC GCA AAG GGG AGG CGA CAC GAG-3'; XRE 3 = 5'-ACT TTC CAG AAG CGG CGC ACG CAA AGC CCA GCT CCG-3'; and Oct-1 = 5'-TGT CGA ATG CAA ATC ACT AGA A-3'.
Western blot analysis of CYP1B1. Proteins were extracted from Jurkat cells using detergents and protease inhibitors (47). Equal amounts of protein were resolved using 4–12% Bis-Tris gels (Invitrogen) as described (47). CYP1B1 was probed using polyclonal rabbit anti-human CYP1B1 antibody (Alpha Diagnostics) as described (47). The expression of ß-actin does not depend on biotin (14). Thus, ß-actin was probed as a control, using a polyclonal goat anti-human ß-actin antibody (Santa Cruz Biotechnology). The relative abundance of CYP1B1 was quantified by gel densitometry (20); data were normalized by the abundance of ß-actin.
CYP1B1 activity. Microsomal extracts were prepared as described (48). CYP1B1 activity in extracts was quantified using the P450-Glo CYP1B1 Assay Kit (Promega). Previous studies suggested that the activity of lactate dehydrogenase does not depend on biotin (49). Thus, the activity of lactate dehydrogenase in whole-cell extracts (50) was quantified as a control (49).
DNA breaks.
Single-stranded DNA breaks were quantified by comet assay (Trevigen). This assay is based on the ability of cleaved DNA fragments to migrate out of the cell under the influence of an electric field, whereas undamaged DNA migrates more slowly and remains within the confines of the nucleoid; strand breaks are associated with a "comet-like" appearance of DNA under the microscope. Samples were stained with a fluorescent DNA intercalating dye (SYBR Green), and DNA was visualized by fluorescence microscopy at the local Microscopy Core Facility (University of Nebraska-Lincoln) according to the manufacturer’s protocol. The occurrence of DNA breaks was evaluated semiquantitatively by visual inspection of images from 
100 cells/treatment group.
Statistical analysis. The paired t test was used to test for significance of differences (51). StatView 5.0.1 (SAS Institute) was used to perform all calculations. Differences were considered significant if P < 0.05. Data are expressed as means ± SD.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-chains of propionyl-CoA carboxylase (molecular mass = 80 kDa) and 3-methylcrotonyl-CoA carboxylase (molecular mass = 83 kDa) migrate as 1 single band on the polyacrylamide gels used here. Previous studies provided evidence that activities of both propionyl-CoA carboxylase and 3-methylcrotonyl-CoA carboxylase depend on the biotin supply in human and animal cells (49). In the present study, holocarboxylases were 2.9 to 3.8 times more abundant in biotin-supplemented cells than in biotin-deficient cells, as judged by gel densitometric analysis of Western blots (Fig. 1B). Increased synthesis of apo-carboxylases may contribute to the increased abundance of holo-carboxylases in biotin-supplemented cells (13). Acetyl-CoA carboxylase was not detectable in cell extracts, consistent with previous studies in Jurkat cells (15).
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CYP1B1 transcription.
The transcriptional activity of the CYP1B1 gene was greater in biotin-supplemented cells compared with biotin-deficient cells. First, transcriptional activity was quantified by using luciferase constructs of the CYP1B1 gene: p1075/+371 (= murine) and 1B1-WT (= human). When Jurkat cells were transfected with murine-derived p1075/+371, luciferase activity was greater in biotin-supplemented cells compared with biotin-deficient cells: 17 ± 1.0 vs. 13 ± 0.5-fold stimulation over empty vector (P < 0.01; n = 3). In contrast, when Jurkat cells were transfected with human-derived 1B1-WT, luciferase activity was similar in biotin-supplemented cells and biotin-deficient cells: 11 ± 1.0 vs. 10 ± 0.5-fold stimulation over empty vector (P > 0.05; n = 3). These findings suggest that biotin-responsive elements upstream or downstream from the region covered by plasmid 1B1-WT (bp –1523 to + 20) might be important for transcriptional regulation in humans (see Discussion). Next, the abundance of CYP1B1 mRNA in Jurkat cells was quantified by Northern blot analysis to confirm biotin-dependent transcription of the CYP1B1 gene in human cells. The abundance of CYP1B1 mRNA was 72% greater in biotin-supplemented cells than in biotin-deficient cells (Fig. 2).
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Next, nuclear extracts were probed with oligonucleotide XRE3 as described for the experiments with XRE2. The pattern observed for XRE3 was similar to the pattern described for XRE2 as follows: 1) biotin did not affect XRE3-binding activity (Fig. 3, lanes o and p); 2) pretreatment with TCDD enhanced nuclear abundance of AhR/ARNT (compare lanes q and r with lanes o and p); and 3) negative controls produced no detectable signal (lanes s–u).
Finally, nuclear extracts were probed with an oligonucleotide containing an Oct-1 consensus sequence (specificity control). The biotin concentration in culture media did not affect the abundance of Oct-1 (Fig. 3, lanes v and w), consistent with previous studies (20). Collectively, these data are consistent with the hypothesis that Sp1/Sp3 (rather than AhR/ARNT) mediate effects of biotin on the transcriptional activity of the CYP1B1 gene.
Western blot analysis.
The increased transcriptional activity of the CYP1B1 gene in biotin-supplemented cells was paralleled by an increased abundance of CYP1B1 protein. The abundance of CYP1B1 in cell extracts was quantified by Western blot analysis and gel densitometry; densities were normalized using ß-actin as a control. The abundance of CYP1B1 was 124% greater in biotin-supplemented cells than in biotin-deficient cells (Fig. 4).
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Single-stranded DNA breaks. DNA breaks occurred more frequently in biotin-supplemented cells than in biotin-deficient cells, as judged by the comet assay (Fig. 5, compare panels A and F). The occurrence of single-stranded DNA breaks increased moderately when the media were supplemented with 17ß-estradiol compared with estradiol-free media (compare panels A and B for representative examples); again, breaks occurred more frequently in biotin-supplemented cells (plus 17ß-estradiol) than in biotin-deficient cells (plus 17ß-estradiol) (compare panels B and G). Treatment of cells with 17ß-estradiol in the presence of the CYP1B1 inhibitor (E)-1-(2,4-dimethoxyphenyl)-2-(3,5-dimethoxyphenyl)-ethene substantially reduced the occurrence of single-stranded DNA breaks (panels C and H), suggesting that the effects of biotin on strand breaks were mediated by CYP1B1. Treatment of cells with TCDD or zeocin (positive controls) caused substantial DNA damage, independently of biotin concentrations in culture media (panels D, E, I, and J).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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There are a few uncertainties associated with the findings presented here. First, we cannot formally exclude the possibility that biotin supplementation decreased the turnover of CYP1B1; theoretically, this would contribute to the increased abundance of CYP1B1 observed in biotin-supplemented cells. Second and most importantly, this study provides no direct evidence concerning whether biotin supplementation enhances cancer risk in vivo in humans. This uncertainty will have to be addressed in epidemiologic studies in humans and in experimental animal models. These future studies will have to consider the following effects of biotin on tumorigenesis and cancer therapy. DNA damage alters the biotinylation pattern in human histones (5,6). Roles for biotinylated histones in response to DNA damage are poorly defined. For example, it is unknown whether biotinylated histones promote apoptosis of damaged cells or whether biotinylated histones mediate DNA repair. Also it is not known whether supplementation with biotin strengthens or weakens the cellular response to DNA damage. Finally, biotin deficiency increases the nuclear translocation of the transcription factor nuclear factor (NF)-
B, mediating survival of cancer cells treated with antineoplastic agents (see below).
The present study and similar recent studies help to estimate human biotin requirements and tolerable upper intake levels. In classical biotin studies, no adverse effects of pharmacologic doses of biotin were noted (1). For example, no overt signs of toxicity were observed in the following persons: patients with inborn errors of biotin metabolism (e.g., biotinidase deficiency) who are empirically treated with biotin doses that exceed the normal dietary intake by 300 times (52); and test subjects treated with acute oral and intravenous doses of biotin that exceeded the dietary biotin intake by up to 600-fold (53). However the following studies suggest that a cautious evaluation of vitamin supplements containing pharmacologic doses of biotin might be warranted.
First, biotin deficiency is associated with increased nuclear translocation of NF-B, enhancing the transcriptional activity of antiapoptotic genes in human lymphoid cells (54). Nuclear translocation of NF-B may impair the efficacy of cancer chemotherapy, based on the following lines of evidence. Cancer cells respond to chemotherapy with nuclear translocation of NF-B (55–57), mediating survival and, thus, resistance to therapy (55,58,59). In preliminary studies, we treated biotin-deficient and biotin-supplemented human lymphoma cells with antineoplastic agents. In those studies, biotin deficiency was associated with increased nuclear abundance of NF-B, increased activity of the anti-apoptotic Bfl-1 gene, and increased survival of lymphoma cells (J. B. Griffin and J. Zempleni, unpublished data).
Second, the expression of transcription factors Sp1 and Sp3 increases in response to biotin supplementation; this is associated with a 76–149% increase in Sp1/Sp3 activity in biotin-supplemented cells compared with biotin-deficient cells (20). This may cause undesired patterns of gene expression such as increased expression of the CYP1B1 gene. Apparently, the effects of biotin on Sp1/Sp3 signaling are not mediated by post-translational modifications of these transcription factors (20).
Third, cell signals other than NF-B and Sp1/Sp3 may also respond to biotin status, e.g., biotinyl-AMP (13) and biotinylation of histones (4). Finally, some biotin catabolites may have biotin-like activities regarding gene expression (60). Collectively, various signaling mechanisms have been identified that mediate effects of biotin and its catabolites on the expression of hundreds of human genes (19,61). These findings must be considered when establishing recommendations for biotin intake and supplementation.
Finally, we would like to comment on the controversial findings concerning transcriptional activities of mouse and human CYP1B1 reporter genes in the present study: the transcriptional activity of the mouse but not the human construct depended on biotin. The human reporter construct used here spans bp –1523 to +20 from the transcription initiation site. Evidence was provided that additional enhancers are located upstream from bp –1523 in the human CYP1B1 gene (21,23). Removal of the region between –2300 and –1356 resulted in a 45% reduction in reporter-gene activity in a previous study (22). Collectively, these findings are consistent with the existence of biotin-responsive enhancers upstream from bp –1523. This hypothesis is corroborated by our observation that the abundance of CYP1B1 mRNA is greater in biotin-supplemented than in biotin-deficient cells.
We conclude that biotin supplementation increases the expression of CYP1B1 in human lymphoid cells. We speculate that biotin has similar effects on the expression of CYP1B1 in nonlymphoid cells, given that CYP1B1 can be detected in most peripheral tissues and in malignant tumors (26,34,35). Consistent with this speculation, the transcription factors Sp1 and Sp3 are ubiquitous in human tissues (45); Sp1 and Sp3 are likely to mediate effects of biotin on CYP1B1 expression, based on the findings presented here. The physiologic significance of increased expression of CYP1B1 in response to biotin supplementation is uncertain. Nevertheless, this study provides evidence that the use of biotin supplements might be associated with undesired patterns of gene expression in humans.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: AhR, aryl hydrocarbon receptor; ARNT, AhR nuclear translocator; CYP1A1, cytochrome P450 1A1; CYP1B1, cytochrome P450 1B1; EMSA, electrophoretic mobility shift assay; NF, nuclear factor; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; XRE, xenobiotic responsive element.
Manuscript received 7 April 2004. Initial review completed 20 May 2004. Revision accepted 2 July 2004.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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