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The biochemical response of rat splenic D-T diaphorase and the histochemical distribution of the enzyme NAD(P)H-NBT reductase to the action of the polycyclic hydrocarbons benz(a)pyrene, 3-methylcholanthrene, 7,12-dimethylbenz(a)anthracene and benz(a)anthracene have been studied. The four polycyclic hydrocarbons tested in this work induced the activity of both enzymes. The stimulation of the D-T diaphorase by benz(a)pyrene is dose dependent and it is partially inhibited by dicumarol. Microsomal and mitochondrial NAD(P)H dehydrogenases are not induced by any of these compounds. The study of the histochemical distribution of the NAD(P)H-NBT reductase shows also a marked increase in the staining of the enzyme which follow a specific pattern, the cells showing the highest activity are the lymphocytes located around the marginal sinus of the white pulp and around follicular arterioles, plus red pulp lymphocytes and myeloblastic cells. The cells in the germinal center show from null to very weak activity. A correlation between the biochemical induction of the soluble D-T diaphorase of the histochemical increase of the NAD(P)H-NBT reductase is attempted.
Virchows Arch B Cell Pathol Incl Mol Pathol 1982
PMID:Rat splenic D-T diaphorase and NAD(P)H-nitroblue tetrazolium reductase. Their use to assess the action of polycyclic hydrocarbons in the lymphatic system. 613 86

The morphology of mammary tumors induced by 7,12-dimethylbenz(a)anthracene in male rats was investigated by light and electron microscopy. All tumors induced in male rats were carcinomas with prominent epithelial growth which shows a medullary or cribriform appearance. Neither mammary dysplasias nor fibroadenomas were induced in male rats. Foci of adenoid cystic carcinoma were encountered in some parts of tumors. Papillary and/or tubular patterns, which have been observed frequently in mammary carcinomas in female rats, were not prominent histologic features in male rats. Secretory activity was not remarkable. The morphology of mammary carcinomas in male rats was unchanged in primary and transplanted tumors under various hormonal conditions. This finding supports our previously published results that the mammary carcinomas in male rats are hormone-independent, although our previous biochemical study revealed that the tumors contain both estrogen and estrogen-dependent progesterone receptors.
Virchows Arch B Cell Pathol Incl Mol Pathol 1984
PMID:Ultrastructure of mammary carcinomas in male rats induced by 7,12-dimethylbenz(a)anthracene. 614 44

The interrelationship between adrenal steroidogenesis and polycyclic aromatic hydrocarbon metabolism has been examined in cultured bovine adrenal cortical (BAC) cells. Adrenocorticotropin (ACTH) selectively induced steroidogenic cytochrome P-450-dependent enzyme activities from BAC cell cultures. In the presence of 10(-7) M ACTH, steroid production requiring 17 alpha-hydroxylation (cortisol + androgens) was increased 5-fold over the formation of 17- deoxysteroids (corticosterone). The effect of 10 microns benz[a]anthracene on steroidogenesis was characterized by suppression of both steroid 17 alpha-hydroxylation (90%) and total steroidogenesis (50%), with a concomitant rise in 17- deoxysteroid formation. The order of stimulation of steroidogenic enzyme activities by ACTH (17 alpha-hydroxylase greater than side chain cleavage greater than 21-hydroxylase) paralleled the order of suppression by benz[a]anthracene. BAC cell cultures incubated with Su-10603, a specific 17 alpha-hydroxylase inhibitor, exhibited similar changes in the pattern of steroidogenesis, as did benz[a]anthracene-treated cells, suggesting that benz[a] anthracene also inhibits steroidogenesis as an inhibitor of 17 alpha-hydroxylase. In addition, benz[a]anthracene induced benzo[a]pyrene metabolism 4- to 6-fold over control levels in these cells. The profile of benzo[a]pyrene metabolites revealed predominantly water-soluble products (nonhydrolyzable greater than sulfates greater than glucuronides), 9,10- monooxygenation products, and 3-phenol. ACTH (10(-7) M) and 0.5 mM cyclic AMP each decreased benzo[a]pyrene metabolism by more than 50%. Both benz[a]anthracene-induced and uninduced benzo[a]- pyrene metabolism were equally reduced in response to ACTH and cyclic AMP. In the presence of 0.2 mM aminoglutethimide, which completely inhibited steroidogenesis, ACTH decreased benz[a]anthracene induction of benzo[a]pyrene metabolism to the same extent as ACTH treatment alone. It is concluded that the suppression of benzo[a]pyrene metabolism by ACTH is mediated by cyclic AMP and does not involve steroids generated in response to ACTH. These studies demonstrate that cytochrome P-450 isozymes involved in steroidogenesis and polycyclic aromatic hydrocarbon metabolism are regulated, in opposing directions, by ACTH.
Mol Pharmacol 1984 May
PMID:The interrelationship of polycyclic hydrocarbon metabolism and steroidogenesis in primary cultures of bovine adrenal cortical cells. 632 66

Metabolism of [3H]-(+/-)-trans-1,2-dihydroxy-1,2-dihydrobenz[a] anthracene by liver microsomes isolated from control, phenobarbital-treated, and 3-methylcholanthrene-treated Long-Evans rats and from 3-methylcholanthrene-treated Sprague-Dawley rats was examined. Liver microsomes from both control and phenobarbital-treated rats metabolized the dihydrodiol at a rate of 0.5 nmol/nmole of cytochrome P450 per minute, whereas prior treatment of rats with 3-methylcholanthrene stimulated the rate of metabolism by 4-fold. Prior treatment of the rats caused marked differences in the regio- and stereoselectivity of the metabolism of this pseudo-diaxial dihydrodiol. In each case, the major metabolites were three bis-dihydrodiols and a pair of diastereomeric 1,2-diol-3,4-epoxides in which the benzylic 1-hydroxyl group is either cis or trans to the epoxide oxygen (diol epoxides-1 and -2, respectively). The presence of the diol epoxides in the incubation medium was inferred from the identification of their corresponding tetraols, which arise by hydrolysis of the diol epoxides on chromatography. Hepatic microsomes from control and phenobarbital-treated rats metabolized the 1,2-dihydrodiol predominantly to 1,2-diol-3,4-epoxides (68-85% of the total metabolites) whereas bis-dihydrodiols represented 28% and 13% of the total metabolites, respectively. In contrast, liver microsomes from 3-methylcholanthrene-treated rats of either strain metabolized the 1,2-dihydrodiol primarily to isomeric bis-dihydrodiols (51-56% of total metabolites), with diol epoxides accounting for only 36-38% of the total metabolites. Bis-dihydrodiol-1 (32-35% of the total metabolites) was formed in greater amounts (2- to 4-fold) than either bis-dihydrodiols-2 or -3, which were formed in about equal amounts and have identical absorption spectra. The ratio of the diastereomeric 1,2-diol-3,4-epoxides-1 and -2 was highly dependent upon the preparation used. For microsomes from control and phenobarbital-treated rats, this ratio was between 3:1 and 4:1 whereas microsomes from 3-methylcholanthrene-treated rats (greater than 70% cytochrome P-450c) gave a ratio of between 1:1.5 and 1:2. The basis for this ratio in the latter case was explained by examination of the products formed from the (+)-(1S,2S)-and (-)-(1R,2R)-enantiomers of the dihydrodiol on metabolism by a highly purified system reconstituted with cytochrome P-450c. The (-)-isomer is a 3-fold better substrate than the (+)-isomer and forms only the diol epoxide-2 diastereomer, whereas the (+)-isomer forms much more diol epoxide-1 than diol epoxide-2 diastereomer.
Mol Pharmacol 1983 Jul
PMID:Regioselectivity and stereoselectivity in the metabolism of trans-1,2-dihydroxy-1,2-dihydrobenz[a]anthracene by rat liver microsomes. 686 20

The enzyme aryl hydrocarbon hydroxylase is present in murine and human cultures of keratinocytes. While the activity of aryl hydrocarbon hydroxylase in murine cultures was found to be inducible after exposure to benz(a)anthracene, human keratinocytes originating from the hair follicle did not respond to this treatment. Hence, cultured human keratinocytes are not suitable for studying the molecular events that mediate the process of aryl hydrocarbon hydroxylase induction.
Mol Biol Rep 1981 Nov 30
PMID:Enzyme induction in cultured human hair follicle cells. 689 75

The lethal and mutagenic effects of methyl methanesulphonate (MMS), ethyl methanesulphonate (EMS), and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) can be dissociated in a mitomycin C (MTC)-sensitive mutant, strain 302, of Micrococcus radiodurans. As regards lethality 302 is extremely sensitive, compared with the wild type, to MTC and decarbamoyl MTC (DCMTC), slightly sensitive to EMS, MNNG, nitrous acid, 7-bromomethylbenz[alpha]anthracene (BrMBA), and N-acetoxy-N-2-acetylaminofluorene (AAAF), and resistant to MMS, hydroxylamine, and ICR 191G. As regards mutability it is, compared to the wild type, very sensitive to MMS, EMS, and MNNG, and slightly sensitive to hydroxylamine and nitrous acid but not to any other agent examined. Alkaline sucrose gradient studies indicate the 302 does not incise DNA containing BrMBA adducts, although it does incise DNA damaged by AAAF but probably not to the same extent as wild type. We put forward the hypothesis that the hypermutability of 302 is due to the non-removal of bases or nucleotides, modified in exocyclic positions, which have altered base-pairing capabilities, while lethality results from the non-removal of bases or nucleotides, also modified in exocyclic positions, which no longer form hydrogen-bonded base pairs.
Mol Gen Genet 1980
PMID:Defective excision repair in a mutant of Micrococcus radiodurans hypermutable by some monofunctional alkylating agents. 693 92

We discuss three important aspects of molecular recognition: steric, electrostatic and hydrophobic. Steric fit means that interacting atoms may not approach each other beyond their van der Waals radii and, simultaneously, crevices should be filled as densely as possible. Electrostatic fit requires the maximum ionic and polar (hydrogen bond or other) interaction between host and guest atoms while the hydrophobic fit corresponds to the association trend between apolar groups in an aqueous medium. Space-filling models, obtained by molecular graphics, illustrate steric complementarity while we use molecular electrostatic potentials (MEPs) and fields (MEFs) to investigate electrostatic and hydrophobic matching. Molecular regions with negative and positive MEPs attract and repel a positive probe charge, respectively, so we consider them as attracting each other. Furthermore we postulate that regions with MEFs of similar magnitude tend to associate more strongly than those with very different fields (similis simili gaudet principle). We apply the above rules to the study of complementarity in the trypsin-BPTI complex and in a crystalline association between styrene epoxide as guest and a camphor-based anthracene derivative as host. We discuss molecular similarity on the same footing as complementarity and give some examples on the application of the concept to the rationalization of relative strengths of trypsin inhibitors.
J Mol Recognit 1993 Dec
PMID:Analysis of molecular recognition: steric electrostatic and hydrophobic complementarity. 752 89

The type I keratin K13, normally restricted to suprabasal cells of internal stratified epithelia, is aberrantly expressed in 7,12-dimethylbenz[a]anthracene (DMBA)-12-O-tetradecanoyl-phorbol-13-acetate-induced murine epidermal tumors and constitutes an early marker of malignant progression. Aberrant K13 expression also occurs in epidermal cell lines derived from DMBA-TPA-induced tumors. As in cultured primary keratinocytes from normal internal stratified epithelia, the in vitro expression of K13 in transformed epidermal cell lines can be induced either by Ca2+ or by retinoic acid (RA). We have found that the promoter of the K13 gene contains a sequence element GGTTCA(N)5TGTTCT, in the following referred to as K13-RARE, that is highly related to the natural retinoic acid responsive element (RARE) of the retinoic acid receptor beta 2 gene. Both elements differ only in the second half-motifs, in which the first and sixth position is occupied by thymidines (K13-RARE) instead of adenines (beta 2-RARE), as well as in their pentameric spacer sequences. Despite this striking homology in the receptor binding domains, we show by transfection of reporter gene constructs of the elements into primary fore-stomach keratinocytes and transformed epidermal cell lines that in both cell systems, unlike beta 2-RARE, the wild-type K13-RARE completely lacks transactivating properties in the presence of RA. A recent hypothesis proposes that aberrant gene expression during tumorigenesis may occur through conversion of inactive response elements with high homology to hormone response elements into functional enhancers by carcinogen-induced point mutations at critical positions (Nawaz et al., Mol. Carcinogen., 7, 76-82, 1993). To investigate whether the aberrantly expressed K13 gene falls into the category of those genes, reporter gene constructs of K13-RARE variants in which either the initial or the terminal thymidine of the second half-motif was replaced by adenine were transfected into epidermal cell lines. Neither mutant exhibited RA-dependent transactivating properties. Strong transactivation could only be achieved by a K13-RARE mutant in which both critical thymidines were substituted by adenines. This type of closely spaced base exchange, unlikely to be created during DMBA initiation of mouse epidermis, was not detectable on sequencing genomic DNA of a squamous cell carcinoma and a transformed epidermal cell line. Instead, in both cases, only the wild-type K13-RARE could be demonstrated. A regulatory role of this RARE-like sequence in the promoter of the murine K13 gene for both normal and aberrant expression of the gene can therefore be excluded.
 ...
PMID:Retinoic acid-induced normal and tumor-associated aberrant expression of the murine keratin K13 gene does not involve a promotor sequence with striking homology to a natural retinoic acid responsive element. 752 98

Stretch-activated channels (SAC) are postulated to regulate cell volume. While this hypothesis is appealing, direct evidence is lacking. Using digital video microscopy, we found that pharmacological blockade of SACs alters the cell volume of isolated rabbit ventricular myocytes during hypoosmotic stress. Under control conditions, relative cell volume increased from 1.0 to 1.311 +/- 0.019 after 10 min in 195 mosmol/l solution. The cation SAC blocker gadolinium (Gd3+; 10 microM) reduced the amount of swelling in hypoosmotic solution by 24% and induced a regulatory volume decrease otherwise not observed. In contrast, the anion SAC blocker 9-anthracene carboxylic acid (9-AC; 1 mM) increased swelling by 44% under the same conditions. Based on the direction of SAC currents, Gd3+ and 9-AC are expected to have opposite effects on cell volume. Furthermore, Gd3+ and 9-AC changed cell volume by only approximately 2% in isosmotic solutions when SACs are expected to be closed. This supports the idea that Gd3+ and 9-AC affect stretch-activated transport processes. In contrast, omitting bath Ca2+ did not alter cell volume under iso- or hypoosmotic conditions suggesting stretch-activated Ca2+ influx is not important in setting cell volume. Not all channels can affect cell volume. Opening ATP-sensitive K+ channels with aprikalim (100 microM) or blocking them with glibenclamide (1 microM) did not alter cell volume under isosmotic or hypoosmotic conditions. These data support the idea that SACs are involved in cardiac cell volume regulation.
J Mol Cell Cardiol 1995 Jan
PMID:Stretch-activated channel blockers modulate cell volume in cardiac ventricular myocytes. 753 86

Transgenic mice carrying the bacterial lacl gene in a lambda shuttle vector were used to isolate and characterize background and 7,12-dimethylbenz[a]anthracene (DMBA)-induced mutations in skin. Adult male mice were treated once topically with either DMBA or acetone or were left untreated. Seven days later, DMBA treatment had significantly increased the mutant frequency in the skin (mean +/- SEM, 36 +/- 3 x 10(-5)) versus in vehicle-treated (6.4 +/- 1.2 x 10(-5)) and untreated mice (7.1 x 1.0 x 10(-5)). At least 10 mutants from each of three DMBA-treated and three untreated mice were selected for DNA sequence analysis. In each case, the entire 1080-bp target gene was sequenced. Base-pair substitutions predominated (86 of 96 mutations), although frameshift and deletion mutations were also detected. Twelve percent of the mutants carried more than one mutation. In controls, the mutations were predominantly GC-->AT transitions (26 of 42), and no AT-->TA transversions were recovered. In contrast, in the DMBA-treated mice, AT-->TA transversions represented 42% of the mutations (23 of 54) and GC-->AT transitions accounted for only 11%. The AT-->TA transversions occurred mostly at 5'-CA sites. This class of mutation has been recovered frequently in ras genes from DMBA-treated mice and probably represents an early event in carcinogenesis (Nelson MA et al., Proc Natl Acad Sci USA 89:6398-6402, 1992). Our present results are consistent with the types of DNA damage induced by DMBA. The observation of different mutant frequencies and spectra in treated and control mice demonstrates the utility of this approach in the study of mutagenesis in vivo.
Mol Carcinog 1995 Sep
PMID:Mutational spectra in the lacl gene in skin from 7,12-dimethylbenz[a]anthracene-treated and untreated transgenic mice. 754 25


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