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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that transformation of Escherichia coli by plasmid DNA modified in vitro by carcinogens leads to RecA-dependant recombination between homologous plasmid and chromosomal DNA sequences. The mechanism of this recombination has now been studied using recombination-deficient mutants, and the influence of induction of the SOS response on the level of recombination investigated. Plasmid pNO1523, containing the str+ operon (Sms), has been modified in vitro by either irradiation with UV light, or by reaction with (+/-) trans-benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) and used to transform streptomycin-resistant hosts. The formation of Ampr transformants which also carry streptomycin resistance was used as a measure of the level of recombination between plasmid and chromosomal DNA. Transformation of recB and recC mutants produced no change in the level of recombination while in the recF mutant a significant decrease was observed compared to the wild type host. Thermal induction of the SOS response in tif-1 and tif-1 umuC mutants followed by transformation led to a four-fold increase in recombination in both cases. The results suggest that the streptomycin-resistant transformants arise exclusively via a recombinational pathway which is largely dependant on the recF gene product, and that this pathway is influenced by induction of the SOS response. These results are discussed in terms of the mechanism of this recombination.
Mol Gen Genet 1985
PMID:Stimulation of recombination between homologous sequences on carcinogen-treated plasmid DNA and chromosomal DNA by induction of the SOS response in Escherichia coli K12. 393 20

The metabolism of benzo(a)pyrene by rabbit liver microsomes can be stimulated or inhibited by 7,8-benzo(a)flavone (ANF) depending on the distribution of specific P-450 enzymes present within the microsomes. Treatment of rabbits with either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or rifampicin leads to an increase of hepatic microsomal metabolism of benzo(a)pyrene. ANF stimulates the rate of benzo(a)pyrene metabolism catalyzed by microsomes isolated from rabbits treated with rifampicin by 3-fold. In contrast, ANF moderately inhibits the activity of microsomes from TCDD-treated rabbits. Variations in the benzo(a)pyrene hydroxylase activity of microsomes from untreated rabbits apparently reflect differences in the expression of P-450 1, a constitutive form of P-450. Thus, the benzo(a)pyrene hydroxylase activity of microsomes from untreated rabbits, which varies from 0.40 to 1.5 nmol/min/mg of protein, is directly correlated with the microsomal concentration of P-450 1. The metabolism of benzo(a)pyrene by microsomes containing high concentrations of P-450 1 is inhibited by a monoclonal antibody specific for this cytochrome to approximately the rate exhibited by microsomes with a low concentration of P-450 1. The benzo(a)pyrene activity stimulated by ANF in microsomes with a low concentration of P-450 1 is not inhibited by the monoclonal antibody. The activity of P-450 1 is inhibited by ANF at concentrations that stimulate other constitutive forms of P-450. Thus, ANF produces offsetting effects on benzo(a)pyrene metabolism in microsomes from untreated animals by stimulating the activity of at least one cytochrome and inhibiting P-450 1-mediated activity.
Mol Pharmacol 1985 Feb
PMID:Variations among untreated rabbits in benzo(a)pyrene metabolism and its modulation by 7,8-benzoflavone. 396 73

Cytotoxic effects of quinones are thought to be mediated by redox cycles between quinones and quinols whereby reactive oxygen species are generated. The role of glucuronidation in preventing these toxic redox cycles was investigated by using benzo(a)pyrene-3,6-quinone and isolated rat hepatocytes or Reuber hepatoma cells (H4IIE). Inhibition of quinol glucuronidation by salicylamide enhanced quinone-dependent oxygen uptake and cytotoxicity. Conjugation of benzo(a)pyrene-3,6-quinol was shown to proceed via the 6-monoglucuronide to the diglucuronide. Diglucuronide formation was low in hepatocytes from untreated controls and phenobarbital-treated rats. However, it was highly stimulated (26-fold) in hepatocytes from 3-methylcholanthrene-treated rats and was also high in Reuber hepatoma cells. Kinetic analysis with liver microsomes indicated that 3-methylcholanthrene-stimulated glucuronidation was due to an increased Vmax of UDP-glucuronosyltransferase which was enhanced 10- and 40-fold or mono- and diglucuronide formation, respectively. These findings suggest that the investigation of quinol glucuronidation (in particular the formation of benzo(a)pyrene-3,6-quinol diglucuronide) is a most useful probe for the 3-methylcholanthrene-inducible isoenzyme(s) of UDP-glucuronosyltransferase. Moreover, this isoenzyme may be particularly suited to protect against toxic redox cycles between benzo(a)pyrene quinones and quinols.
Mol Pharmacol 1985 Apr
PMID:Protection against toxic redox cycles between benzo(a)pyrene-3,6-quinone and its quinol by 3-methylcholanthrene-inducible formation of the quinol mono- and diglucuronide. 398 90

Mouse liver cytosol contains saturable, high-affinity binding sites for the aromatic carcinogen benzo[a]pyrene that are distinct from the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-binding aryl hydrocarbon receptor. Specific binding parameters determined by an equilibrium binding assay indicate a dissociation constant of 7.7 nM and a binding capacity of 4.7 pmol of benzo[a]pyrene per milligram of cytosolic protein. Although the data best fit a single class of binding sites by Scatchard and Hill analyses, discrete 4 S and 9 S [3H]benzo[a]pyrene peaks are identified on sucrose density gradients comprising about 98% and 2% of the specific binding, respectively. Steroid hormones and other ligands for previously described binding proteins have no effect on the specific carcinogen binding when present in the cytosol incubation at saturating levels. The glutathione S-transferases, shown in rat and human liver to possess carcinogen-binding properties, were also found not to be responsible for this receptor-like benzo[a]pyrene binding in mouse liver cytosol. Competition binding studies indicate that other aromatic hydrocarbon compounds of a structure similar to that of benzo[a]pyrene are equipotent in affinity for this major carcinogen-binding site.
Mol Pharmacol 1984 Sep
PMID:Carcinogen-binding proteins. High-affinity binding sites for benzo[a]pyrene in mouse liver distinct from the Ah receptor. 609 Aug 86

Exposure to polychlorinated biphenyl compounds (PCBs) has resulted in a variety of cutaneous effects in several species. When mice were exposed to PCBs through the diet and to benzo-(a)-pyrene (BAP) by topical application, hyperkeratinization occurred in the epidermis and hyperkeratinized cysts occasionally formed, but alterations were also observed in the dermis and in small cutaneous blood vessels, particularly capillaries and venules. The luminal borders of the endothelial cells often became irregularly ruffled, and pinocytotic vesicles increased in number and varied considerably in size. Subjacent to the endothelium and pericytes, the basal laminae were either replicated many times or extensively thickened. These effects were attributable to PCBs but not to BAP with the methods and dosages employed. Although endotheliocytosis has been reported in birds exposed to PCBs, vascular effects have not been previously described in mammals treated with these compounds.
Virchows Arch B Cell Pathol Incl Mol Pathol 1983
PMID:Ultrastructural features of the murine cutaneous microvasculature after exposure to polychlorinated biphenyl compounds (PCBs) and benzo-(a)-pyrene (BAP). 613 87

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 covalent binding of the ultimate carcinogen (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo [alpha]pyrene (BPDE) to enriched ovalbumin messenger RNA (mRNAov) of known sequence was examined. Incubation of mRNAov with elevated concentrations of labeled BPDE in TE buffer (0.02 M Tris X HCl, 1 mM EDTA, pH 7.2) containing 0.1 M KCl and 10 mM MgCl2 resulted in approximately 30 BPDEs covalently bound per RNA molecule. Covalent binding in the absence of KCl and MgCl2 resulted in a significant increase in binding to 110 BPDEs bound per molecule or modification of 12% of the total guanosine and adenosine nucleotides present. The nucleoside adducts formed were nearly all guanosine and adenosine in a ratio of 1.6:1.0. It was also observed that digestion of mRNAov with T2 RNase prior to reaction with BPDE resulted in a 52% decrease in guanosine adduct formation and a 93% decrease in adenosine adducts compared with undigested controls. Comparison of the binding of labeled BPDE to 18 S and 28 S ribosomal RNAs and to mRNAov revealed that the guanosine adduct to adenosine adduct ratio and the number of BPDEs bound increased with increasing G-C content. The results reported here show that ionic composition of the medium, G-C content, and the presence of a polymeric state can significantly influence the quantitative and/or qualitative nucleoside BPDE adducts formed.
Mol Pharmacol 1984 Sep
PMID:Factors influencing the covalent binding of (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene to ribonucleic acids. 620 22

Epithelial keratinization in fragments of fetal rat forestomach in organ culture was significantly accelerated by treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 1 h (Fukamachi and Takayama 1979). In this paper, we examined whether acceleration of epithelial keratinization may be characteristic for some carcinogens, and also the mechanism of acceleration of epithelial keratinization by treatment with MNNG. Forestomach epithelial keratinization was accelerated by treatments with 4-nitroquinoline-1-oxide, N-acetoxy-2-acetylaminofluorene, 1-methyl-1-nitrosourea, 7,12-dimethylbenzanthracene, methyl methanesulfonate, and MNNG, but not with 2-acetylaminofluorene, pyrene, or dimethylsulfoxide, indicating that carcinogens may specifically accelerate epithelial keratinization. Chemicals that accelerated epithelial keratinization inhibited epithelial mitotic activity on day 1 in culture, but the mitotic rate was restored to the control level from day 2 onwards. The epithelial keratinization was completely inhibited by adding 5 micrograms/ml of retinoic acid (RA) to the culture medium, irrespective of treatment with MNNG. Addition of 1 microgram/ml of RA suppressed epithelial keratinization in control explants more than in MNNG-treated explants. One possible explanation is that the epithelial cells become less sensitive to RA after MNNG-treatment. A mechanism is proposed assuming that carcinogens induce some qualitative changes in epithelial cells by inhibiting cell proliferation on day 1 in culture, and consequently the epithelial keratinization is accelerated.
Virchows Arch B Cell Pathol Incl Mol Pathol 1984
PMID:Acceleration of epithelial keratinization by carcinogens in fetal rat forestomach in organ culture. 620 61

Inclusion of calf thymus DNA during microsomal benzo[a]pyrene (BP) metabolism increases product formation by decreasing the accessibility of microsomal enzymes to inhibitory BP quinones. The relief of product inhibition of BP metabolism, the stimulation of the formation of BP 7,8-dihydrodiol-9,10-oxides (DE), and the corresponding DNA adducts were all dependent to varying extents on DNA concentration. The role of BP quinones was evidenced by effects of DNA on all aspects of quinone reactivity: (a) inhibition of microsomal reduction of quinones, (b) inhibition of quinone glucuronidation, (c) inhibition of quinone monooxygenation, (d) a substantial reduction of the inhibition of BP metabolism and diol epoxide (DE) formation by added BP 6,12-quinone, and (e) a stimulation of BP metabolism even though quinine levels were also increased. DNA inhibited the reduction of 1,6- and 3,6-quinone to a similar degree under both oxygen-depleted and aerobic conditions. Other effects of DNA were very selective; glucuronidation of added 1,6- and 6,12-quinone was inhibited less than glucuronidation of 3,6-quinone (35% and 50% versus over 80%). However, monooxygenation of 3,6-quinone was not inhibited, whereas monooxygenation of 1,6-quinone was reduced by 60-70%. There was no measurable monooxygenation of 6,12-quinone. This specificity may indicate that DNA exerts its effect not simply by sequestering BP quinones. The interaction with DNA produced a distinct 25-nm red shift in the visible spectra of 1,6- and 3,6-quinone, while the change in the 6,12-quinone spectrum was less pronounced. RNA induced a similar red shift in the 1,6-quinone spectrum. Spectral measurements indicated binding of one molecule of 1,6-quinone per 50 DNA base pairs, while binding to RNA was 10-fold less extensive. The binding of 1,6-quinone to DNA was decreased by Mg2+, suggesting that 1,6-quinone binds by intercalation. DNA perturbs BP metabolism in a second way by increasing the ratio of 9-phenol to 9,10-dihydrodiol 4-fold. This is probably due to a DNA-catalyzed rearrangement of 9,10-oxide to 9-phenol. This effect contributes substantially to the greater sensitivity of the formation of 9-phenol 4,5-oxide-DNA adducts to the DNA concentration. It is evident from these data that, in addition to binding carcinogens covalently, DNA can affect the kinetics and product distribution of carcinogen metabolism. The high capacity of DNA to sequester BP quinones from cellular membranes is likely to be associated with additional DNA damage which may contribute to carcinogenesis.
Mol Pharmacol 1983 May
PMID:Modulation of microsomal benzo[a]pyrene metabolism by DNA. 630 33

Simian virus 40 (SV40)-transformed Syrian hamster kidney cells produce infectious SV40 virus particles after treatments which damage DNA, such as UV irradiation or mitomycin C treatment. We have found that the induction of SV40 by DNA-damaging agents is greatly stimulated when a typical tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA), is present in the medium. Phorbol, which has a molecular structure similar to TPA but does not have any tumor-promoting activity, showed no such stimulatory effect on SV40 induction. This apparent synergistic effect of DNA-damaging agents and tumor promoter (TPA) was more pronounced when a tumor initiator, benzo [a]pyrene or 2-acetamido-fluorene, was combined with TPA. The effect of TPA on UV-triggered SV40 induction was greatly influenced by the timing of TPA addition to the culture medium, which was most efficient when addition of TPA was 5 to 20 h before UV irradiation. The effect of TPA, however, was not observed in SV40 rescue from hamster cells by cell fusion with permissive monkey (C7) cells.
Mol Cell Biol 1983 May
PMID:Tumor promoter 12-O-tetradecanoylphorbol 13-acetate stimulates simian virus 40 induction by DNA-damaging agents and tumor initiators. 630 45


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