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PubMed1999

Circadian expression of the steroid 15 alpha-hydroxylase (Cyp2a4) and coumarin 7-hydroxylase (Cyp2a5) genes in mouse liver is regulated by the PAR leucine zipper transcription factor DBP.

To study the molecular mechanisms of circadian gene expression, we have sought to identify genes whose expression in mouse liver is regulated by the transcription factor DBP (albumin D-site-binding protein). This PAR basic leucine zipper protein accumulates according to a robust circadian rhythm in nuclei of hepatocytes and other cell types. Here, we report that the Cyp2a4 gene, encoding the cytochrome P450 steroid 15alpha-hydroxylase, is a novel circadian expression gene. This enzyme catalyzes one of the hydroxylation reactions leading to further metabolism of the sex hormones testosterone and estradiol in the liver. Accumulation of CYP2A4 mRNA in mouse liver displays circadian kinetics indistinguishable from those of the highly related CYP2A5 gene. Proteins encoded by both the Cyp2a4 and Cyp2a5 genes also display daily variation in accumulation, though this is more dramatic for CYP2A4 than for CYP2A5. Biochemical evidence, including in vitro DNase I footprinting on the Cyp2a4 and Cyp2a5 promoters and cotransfection experiments with the human hepatoma cell line HepG2, suggests that the Cyp2a4 and Cyp2a5 genes are indeed regulated by DBP. These conclusions are corroborated by genetic studies, in which the circadian amplitude of CYP2A4 and CYP2A5 mRNAs and protein expression in the liver was significantly impaired in a mutant mouse strain homozygous for a dbp null allele. These experiments strongly suggest that DBP is a major factor controlling circadian expression of the Cyp2a4 and Cyp2a5 genes in the mouse liver.

Animals↗
PubMed1982

Teratogenicity of di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) in mice.

Di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) were mixed with diet at graded levels of 0.05, 0.1, 0.2. 0.4 and 1.0 wt-% and given to pregnant ICR mice throughout gestation. Maternal weight gain was suppressed and fetal resorption increased at 0.2, 0.4 and 1.0% levels of DEHP and 1.0% level of DBP. All the implanted ova died early in rats fed 0.4 and 1.0% levels of DEHP. External malformations increased significantly by 0.2% DEHP, and 1.0% DBP showed borderline significance. The major malformations in treated groups were neural tube defects (exencephaly and myeloschisis), suggesting that the phthalic acid esters (PAEs) affect neural tube closure in developing embryos. Treatment with the compounds caused intrauterine growth retardation and delayed ossification with an apparently dose-related response pattern. These results indicate that a high dose of DEHP and DBP might be embryotoxic and teratogenic in mice. The maximum nonembryotoxic doses of PAEs in mice were more than 2000 times the estimated level of human intake through the food chain. Thus it is assumed that the current "normal" exposure level of PAEs dose not pose an imminent threat to human fetal development.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

[Genotypes of vitamin-D-binding protein (DBP) in patients with chronic obstructive pulmonary disease and healthy population of Republic Bashkortostan].

The distribution of alleles and genotypes of vitamin D-binding protein (DBP) gene has been studied in patients with Chronic Obstructive Pulmonary Disease (COPD, n = 298) and healthy individuals (n = 237) from two ethnic groups (Tatars and Russians) living in Republic Bashkortostan. Statistically significant differences in the distribution of DBP gene genotypes between Tatars and Russians (chi2 = 8.854, df = 5, P = 0.04) were revealed. The pattern of allele's distribution within DBP gene was similar in healthy control subjects of both ethnic groups, with gradient reduction in row GC*1S> GC*1F> GC*2. The most common genotypes were: GC*1F/1S in Tatars (36.79%) and GC*1S/2 in Russians (34.62%). It has been shown, that Tatars with genotype GC*1F/1S have a lower risk of COPD development: the frequency of GC*1F/1S genotype in COPD patients was significantly lower than in healthy individuals (19.85% versus 36.79%; chi2 = 7.622, P = 0.0067, Pcor = 0.0335; OR = 0.42 CI 95% 0.22-0.79). At the same time, COPD patients from the same group had higher frequency of GC* 1F/2 genotype than healthy individuals (19.08% versus 8.49%; chi2 = 4.52, P = 0.033, Pcor = 0.165; OR = 2.54 CI 95% 1.067-6.20). In Russian population the distribution of alleles and genotypes of DBP gene were similar in COPD patients and healthy individuals.

Aged↗
PubMed1991

Genetic polymorphism of the vitamin D-binding protein (DBP) in crab-eating macaques (Macaca fascicularis).

Vitamin D-binding protein (DBP) of crab-eating macaques (Macaca fascicularis) was examined by means of three electrophoretic methods. DBP phenotypes were observed to be one or two bands in each method. All of DBP molecular variants could be detected by the simultaneous typing with these three methods. Family analysis suggested that DBP variants followed the mode of autosomal codominant inheritance. A total of 17 phenotypes governed by at least 11 alleles were observed in the populations of Malaysia, Indonesia, and the Philippines. The genetic variability was high in Malaysian and Indonesian populations but low in the Philippine population.

Alleles↗
PubMed1998

DBP binds to the proximal promoter and regulates liver-specific expression of the human angiotensinogen gene.

Angiotensinogen is the glycoprotein precursor of one of the most potent vasoactive hormones, angiotensin-II. It has been shown recently that an ATF like element (ALE) located between bases -102 and -87 of the human angiotensinogen gene plays an important role in liver specific expression of this gene and binds to CREB/ATF family of transcription factors and a novel factor (ALF). We show here that this sequence binds to the liver enriched transcription factor DBP and cotransfection of expression vector CMV-DBP increases the expression of reporter constructs containing this sequence. In addition, we show that transcription factor C/EBP-delta binds to this sequence and an expression vector containing C/EBP-delta coding region increases the expression of reporter constructs containing this sequence. Since DBP is involved in circadian rhythm, our studies suggest that this sequence may be involved in circadian expression of the human angiotensinogen gene.

Activating Transcription Factors↗
PubMed2003

Adenovirus DNA replication: protein priming, jumping back and the role of the DNA binding protein DBP.

The adenovirus (Ad) genome is a linear double-stranded (ds) molecule containing about 36 kilobase pairs. At each end of the genome an approximately 100 base pair (bp) inverted terminal repeat (ITR) is found, the exact length depending on the serotype. To the 5'-end of each ITR, a 55-kDa terminal protein (TP) is covalently coupled. The Ad DNA replication system was one of the first replication systems that could be reconstituted in vitro (Challberg and Kelly 1979). The system requires three virally encoded proteins: precursor TP (pTP), DNA polymerase (Pol) and the DNA binding protein (DBP). In addition, three stimulating human cellular proteins have been identified. These are the transcription factors NFI (Nagata et al. 1982) and Oct-1 (Pruijn et al. 1986) and the type I topoisomerase NFII (Nagata et al. 1983). Ad DNA replication uses a protein primer for replication initiation. The transition from initiation to elongation is marked by a jumping back mechanism (King and van der Vliet 1994), followed by elongation. In order to elongate DBP is required. In this review we discuss the roles of DBP during initiation and elongation and we relate biochemical data on the jumping back mechanism used by Ad Pol to the recently solved crystal structure of a Pol alpha-like replication complex (Franklin et al. 2001). We comment on the conditions and possible functions of jumping back and propose a model to describe the jumping back mechanism.

Adenoviridae↗
PubMed1990

Testicular effects of di-n-butyl phthalate (DBP): biochemical and histopathological alterations.

Di-n-butyl phthalate (DBP) was administered to young male rats by gavage at the doses of 250, 500 and 1,000 mg/kg body weight/day for 15 days. A significant decrease in testes weight was observed at 500 and 1,000 mg/kg doses of DBP. Histopathological examination revealed marked degeneration of seminiferous tubules. The activities of testicular enzymes associated with postmeiotic spermatogenic cells, such as sorbitol dehydrogenase and acid phosphatase, were decreased significantly, while that of lactate dehydrogenase was significantly increased, coincident with degeneration of spermatogenic cells. The activities of enzymes associated with premeiotic spermatogenic cells, Sertoli cells or interstitial cells, beta-glucuronidase, gamma-glutamyl transpeptidase and glucose-6-phosphate dehydrogenase were significantly increased. Thus the alterations in activity of these testicular cell specific enzymes suggest that DBP exposure during early life could affect the testicular functions.

Animals↗
PubMedDate not supplied

The phthalate diesters DEHP and DBP do not induce lauric acid hydroxylase activity in rainbow trout.

Aquatic organisms are extensively exposed to phthalate esters. We have investigated in trout the effects of diethylhexylphthalate (DEHP) and dibutylphthalate (DBP) on xenobiotic metabolizing enzymes which have been suggested as possible environmental biomarkers. Rainbow trout (Oncorhynchus mykiss) were waterborne exposed to DEHP (1 mg/l) or DBP (0.1 or 1 mg/l) for 72 h. Another group of rainbow trout received daily for 3 days an intraperitoneal injection of 50 mg/kg of DEHP or DBP. Laurate hydroxylation, ethoxyresorufin-o-deethylation, UDP-glucuronyltransferase activity and glutathione-S-transferase activity were measured in liver and extrahepatic tissues. The phthalate esters have been found not to induce these enzymes; in particular, the results do not support the previously described induction of lauric acid hydroxylase in sea bass treated with DEHP [Comp. Biochem. Physiol. B122 (1999) 253.].

Animals↗
PubMed1997

Role of the liver-enriched transcription factors C/EBP alpha and DBP in the expression of human CYP3A4 and CYP3A7.

In the human fetal liver, CYP3A7 is expressed as early as the 13th week of gestation. This continues to the perinatal period when it is sharply repressed prior to birth. Concomitantly, the expression of CYP3A4, not detectable in the fetus, sharply increases in the perinatal period to remain elevated throughout adulthood. The mechanisms controlling these developmental patterns of expression have not yet been elucidated at the molecular level. The aim of the present work was to make a functional analysis of the 5'-flanking regions of CYP3A4 and CYP3A7 in different cell lines, including CHO, HepG2, WRL68 and Caco-2 TC7, after cotransfection with two hepato-specific transcription factors, C/EBP alpha and DBP. Six deletions of different length of the 5'-flanking region of each gene, spanning from -1240 to +11 for CYP3A4 and from -1157 to +13 for CYP3A7, were analysed by reporter gene assay. With the CYP3A4 constructs, C/EBP alpha stimulated the transcriptional activity in CHO cells in a way that suggested the presence of at least two C/EBP alpha-responsive elements, one downstream of -55 and one upstream of this position. In CYP3A7, the proximal element exhibited comparable stimulation to the corresponding one in CYP3A4, although the more distal one appeared to respond to a much smaller extent. CYP3A4 and CYP3A7 constructs also responded to C/EBP alpha in HepG2 and WRL68. However, only CYP3A4 and not CYP3A7 was transactivated by this factor in the Caco-2-TC7 cell line. In CHO cells, only the shortest proximal promoter deletion of CYP3A4 (downstream of -57) responded to DBP, while neither the longer constructs nor the CYP3A7 deletions were transactivated. Although preliminary, our results suggest that C/EBP alpha, and possibly other members of the C/EBP family, play a prominent part in the expression of the CYP3A family in man, and that the two genes respond differently to C/EBP alpha and DBP, two factors that exhibit a strict proliferation-dependent pattern of expression in the liver.

Animals↗
PubMed2000

Effects of di-n-butyl phthalate (DBP) on male reproductive development in the rat: implications for human risk assessment.

The National Toxicology Program (NTP) conducted a continuous breeding study in SD rats with di-n-butyl phthalate (DBP) given via the diet at dose levels of up to 650 mg/kg/day. In the parental generation effects on reproduction were modest (small decreases in litter size and pup weight following treatment). However, the F(1) male offspring had marked decreases in fertility (at 650 mg/kg/day), with reduced sperm counts and reproductive tract malformations on reaching adulthood. A no-observed-adverse-effect level (NOAEL) was not established for the study [lowest-observed-adverse-effect level (LOAEL) 66 mg/kg/day]. In a study conducted at CIIT, the majority of these adverse changes could be reproduced over a similar dose range, but with a much shorter dosing regimen covering a critical window of development (gestation days 12-20). A default risk assessment for DBP indicates a reference dose (RfD) of 66 microg/kg/day, based on a LOAEL of 66 mg/kg/day and default factors of 10 for inter-species and inter-individual differences and the lack of a NOAEL. Human exposure data would indicate worst-case scenarios to infants (via formula) in the dose range of the RfD. A default risk assessment appears to be inappropriate since rodents, unlike primates, metabolize phthalate diesters (including DBP) to monoesters extensively in the gut following oral administration. It is believed that the monoester is the active principle for induction of reproductive and developmental toxicity of specific phthalate esters. Thus, if humans produce very low levels of the monoester from an environmental exposure to the diester, the likelihood of any reproductive or developmental toxicity via the oral route appears extremely remote.

Animals↗
PubMed1986

The clinical applications of demineralised bone powder (DBP)-induced osteoneogenesis.

New bone tissue can be induced anywhere in the animal organism, i.e. even at a site distant from actual bone, by the implantation of demineralised bone powder (DBP). Basic implantation experiments were first carried out and tested in the rat (Bettex-Galland 1985). The results led us to use the experience gained to treat four patients with bone defects with DBP (one bone cyst, and 3 chronic skull defects). The DBP used was prepared aseptically from fresh cadaver bone. The results were assessed by means of x-ray films and/or CT-scan, and the preliminary evaluation is encouraging.

Adolescent↗
PubMed1989

Fatty acids bound to vitamin D-binding protein (DBP) from human and bovine sera.

Human and bovine vitamin D-binding protein (DBP) have been isolated from serum by a method that does not involve denaturing steps. This method includes Cibacron Blue-Sepharose chromatography, gel filtration, DEAE-Sephadex chromatography and albumin immunoadsorption. Analysis of fatty acids bound to the isolated human and bovine DBP showed molar ratios of fatty acid to protein of 0.4 and 1.3 respectively meanwhile human and bovine albumin have bound 1.8 and 1.5 moles per mol respectively. Most of fatty acids bound to human and bovine DBP are monounsaturated and saturated, mainly oleic and palmitic acids, which together account for 50% of the total of fatty acids in both species. By contrast, polyunsaturated fatty acids represented a minor component, less than 5%.

Animals↗
PubMed1993

Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP).

Human vitamin D binding protein (DBP) displays considerable polymorphism with 120 described alleles. Among these, three alleles are frequently observed, Gc 1F (pI 4.94-4.84), Gc 1S (pI 4.95-4.85) and Gc 2 (pI 5.1). Differences between these genetic forms of the protein in affinity for vitamin D metabolites have been detected by electrophoretic methods. The constant affinity (Ka) values determined in this study confirm these differences. The affinities of six rare variants were also examine. Those of the DBP genetic forms to the vitamin D derivatives 25-OH-D3 and 1,25-(OH)2-D3 seem to be related to the isoelectric point of the proteins: a high affinity corresponding to a low isoelectric point. The Gc 1A9 and 1A11 mutants were associated with higher affinity for the vitamin D derivatives and the Gc 1C1 and 1C21 mutants were deficient.

Calcifediol↗
PubMed2005

Effects of bisphenol-A (BPA), dibutylphtalate (DBP), benzophenone-2 (BP2), procymidone (Proc), and linurone (Lin) on fat tissue, a variety of hormones and metabolic parameters: a 3 months comparison with effects of estradiol (E2) in ovariectomized (ovx) rats.

The endocrine active substances BPA, DBP and BP2 have estrogenic effects in the uterus. Proc and Lin were shown to be antiandrogenic. Whether other estrogen-regulated parameters like lipids, fat metabolism and hormones are also affected by these substances is unknown. We compared the effects of a 3 months lasting administration of these substances with those of E2 on an estrogen-regulated fat depot and on serum TSH, T3, T4, LH, and lipid concentrations. BP2 shared many of the effects of E2 by suppressing LH, cholesterol, LDL, HDL and the size of a small estrogen-regulated fat depot in the lower hindleg. BP2 suppressed T4 but not T3 and TSH. The effects of DBP and BPA were mostly negligible whereas Lin and Proc also reduced the fat depot and serum leptin but increased triglycerides and serum lipids. Serum T3 and T4 concentrations were reduced by Lin and Proc. These data indicate that BP2 has similar, though slightly weaker effects as E2 whereas the effects of Proc and Lin differ from those of E2 on serum lipids and hormones. BP2 can be regarded as an estrogenic endocrine active substance whereas the effects of Lin and Proc appear not to involve estrogen receptors.

Adipose Tissue↗
PubMed2004

Biosynthesis of di-(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) from red alga--Bangia atropurpurea.

The contents of di-(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) of red alga, Bangia atropurpurea, filaments cultured in artificial sea water medium were similar to those cultured in natural sea water medium. In the culture experiment, B. atropurpurea filaments were found to synthesize de novo phthalate esters. Additionally, DEHP and DBP contents in different species of algae grown in the same environment were different significantly, suggesting that it was due to the intrinsic nature of algae.

Culture Media↗
PubMed2001

DBP formation kinetics in a simulated distribution system.

Little is known about how the growth of halogenated disinfection by-products (DBPs) in drinking water is affected by time spent in a distribution system. Experiments were performed to compare the rate of trihalomethane and haloacetic acid production in a simulated pipe environment to that observed for the same water held in glass bottles. Results showed that although the rate of chlorine consumption in the pipe was much greater than in the bottle, there was no decrease in the amount of haloacetic acids produced and that trihalomethane levels actually increased by an average of 15%. Separate tests confirmed that this increase was due to a reservoir of organic precursor material associated with deposits on the pipe wall. This work suggests that the rate of DBP production in a distribution system will not necessarily be reduced by increased chlorine consumption due to non-DBP producing reactions with deposits on the pipe wall.

Bromides↗
PubMed1993

Synergy between transcription factors DBP and C/EBP compensates for a haemophilia B Leyden factor IX mutation.

Haemophilia B Leyden is characterized by low childhood levels of factor IX which gradually increase after puberty, eventually resulting in a return to health. The disease is the result of single nucleotide substitutions within a 40 bp region encompassing the major transcriptional start site. We have characterized transcription factor binding sites within the factor IX promoter. Five sites were identified and a Leyden mutation at nucleotide -5 was shown to interfere with the binding of proteins to one of three newly identified sites. The correlation between the post-pubertal recovery of these mutants and the induction of the transcription factor DBP led us to the discovery of a synergistic interaction between DBP and C/EBP responsible for the recovery of normal transcriptional activity of the -5 mutant promoter and may play a role in the resolution of other Leyden mutants.

Adolescent↗
PubMed2006

Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions.

Mammalian circadian rhythms are based on transcriptional and post-translational feedback loops. Essentially, the activity of the transcription factors BMAL1 (also known as MOP3) and CLOCK is rhythmically counterbalanced by Period (PER) and Cryptochrome (CRY) proteins to govern time of day-dependent gene expression. Here we show that circadian regulation of the mouse albumin D element-binding protein (Dbp) gene involves rhythmic binding of BMAL1 and CLOCK and marked daily chromatin transitions. Thus, the Dbp transcription cycle is paralleled by binding of BMAL1 and CLOCK to multiple extra- and intragenic E boxes, acetylation of Lys9 of histone H3, trimethylation of Lys4 of histone H3 and a reduction of histone density. In contrast, the antiphasic daily repression cycle is accompanied by dimethylation of Lys9 of histone H3, the binding of heterochromatin protein 1alpha and an increase in histone density. The rhythmic conversion of transcriptionally permissive chromatin to facultative heterochromatin relies on the presence of functional BMAL1-CLOCK binding sites.

ARNTL Transcription Factors↗