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J DiGiovanni

Publications and source records attributed to J DiGiovanni.

At least 145 records · Page 8Linked to original sources
PubMed1979

The importance of the "bay region" diol-epoxide in 7,12-dimethylbenz[a]anthracene skin tumor initiation and mutagenesis.

The skin tumor-initiating and V79 mutagenic activities of various derivatives of 7,12-dimethylbenz[a]anthracene (DMBA) were investigated to determine what possible cellular metabolite(s) may be responsible for its carcinogenicity and/or mutagenicity. 1-,2-,3-,4- and 5-hydroxyDMBA were found to be essentially inactive as skin tumor initiators whereas 9- and 10-hydroxyDMBA had weak activity. The (+/-)-trans DMBA 8,9- and 5,6-dihydrodiols were also essentially inactive as skin tumor initiators and (+/-)-DMBA 8beta,9alpha-diol-10alpha-11alpha-epoxide had weak skin tumor initiating activity. All of the above tested derivatives of DMBA were essentially inactive as mutagens in the cell-mediated or direct V79 mutagenesis systems. A methyl or fluoro addition to the 1, 2 or 5 positions almost completely blocked the skin tumor initiating and V79 mutagenic activities of DMBA, whereas a fluoro addition to position 11 did not. From our data we suggest that a 'bay region' diol-epoxide may be important in DMBA carcinogenicity and mutagenicity.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1979

Covalent binding of polycyclic aromatic hydrocarbons to adenine correlates with tumorigenesis in mouse skin.

Mouse epidermal homogenates were utilized to convert various polycyclic aromatic hydrocarbons to metabolites capable of binding covalently with nucleic acids. Poly(G) showed the highest capacity to bind covalently with the hydrocarbons; however, there was no correlation between binding to poly(G) and mouse skin tumorigenicity. On the other hand, covalent binding to poly(A) correlated well with values obtained for binding to DNA and mouse skin tumorigenicity. The order of binding to poly(A) was; 7,12-dimethylbenza[a]anthracene greater than benzo[a]pyrene greater than dibenz[a,h]anthracene greater than dibenz[a,c]anthracene.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1979

Potent tumor-initiating activity of the 3,4-dihydrodiol of 7,12-dimethylbenz(a)anthracene in mouse skin.

The abilities of the racemic trans-3,4-, 5,6-, and 8,9-dihydrodiols of 7,12-dimethylbenz(a)anthracene to initiate skin tumors in mice were determined by using a two-stage system of tumorigenesis. The 7,12-dimethylbenz(a)anthracene trans-3,4-dihydrodiol was found to be much more active as a tumor initiator than the parent hydrocarbon. The 7,12-dimethylbenz(a)anthracene trans-5,6- and 8,9-dihydrodiols were essentially inactive as skin tumor initiators. Our results suggest that the 3,4-dihydrodiol of 7,12-dimethylbenz(a)anthracene is a proximal carcinogen and that the "bay region" diol-epoxide may be the ultimate carcinogenic form of DMBA.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1978

Lack of tumor-promoting ability of certain environmental chemicals in a two-stage mouse skin tumorigenesis assay.

The food antioxidants butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) were tested as tumor promoters on CD1 female mice initiated with 7, 12-dimethylbenz(a)anthracene (DMBA). At a dose of 1 mg twice weekly they did not promote skin tumors. Nor did they produce tumors when tested as a complete carcinogen without DMBA initiation. The polychlorinated biphenyl Aroclor 1254 (PCB) and the polybrominated biphenyl Firemaster-6 (PBB) were also tested for their ability to promote skin tumors; at a 100 microgram dose twice weekly they were inactive. The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at a dose of 0.1 microgram twice weekly did not promote skin tumors in DMBA-initiated mice. TCDD, PCB, and PBB did not promote spontaneous tumors. None of the compounds at the dosages tested significantly increased the intrafollicular epidermis, nor did they appear to be chronically toxic to the test animals. These results indicate that dosage may be an important factor in promotion, since several of the tested compounds are known to be promoters in pulmonary and hepatic systems.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1977

Effect of trichloropropene oxide on the ability of polyaromatic hydrocarbons and their "K-region" oxides to initiate skin tumors in mice and to bind to DNA in vitro.

The potent epoxide hydrase inhibitor, 1,1,1-trichloro-2,3-propene oxide (TCPO), enhanced the tumor-initiating ability of benzo[alpha]pyrene (BP) and 3-methylcholanthrene (MCA) but had no effect on 9,10-dimethyl-1,2-anthracene (DMBA) initiation in a two-stage system of tumorigenesis in female Charles River CD-1 mice. The tumor-initiating ability of dibenz[alpha,h]-anthracene (DBA) was decreased by prior topical treatment with 10 mumoles of TCPO. The tumor latency period of BP and MCA was decreased by TCPO but had no effect on DMBA or DBA. Topical treatment with 10 mumoles of TCPO did not initiate tumors in a two-stage system in mouse skin nor did it cause any histopathologic changes in the skin. The "K-region" epoxides of BP, DMBA, and MCA were weak tumor initiators when compared to the parent compounds. TCPO only slightly increased or had no effect on the tumor-initiating activity of the above epoxides. Pretreatment with Croton oil 18 hours prior to initiation with BP-4,5-epoxide also slightly enhanced the tumorigenic response in mouse skin. DBA-5,6-epoxide, when tested as a complete carcinogen at high doses (1 mg daily/10 days), was found to be a weak carcinogen but with activity comparable to that of DBA. TCPO only slightly increased the in vitro epidermally mediated covalent binding of the above parent polycyclic hydrocarbons to DNA.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1976

Some biological properties and an in vivo evaluation of tyrosine phenol-lyase on growth of B-16 melanoma.

Tyrosine phenol-lyase from Erwinia herbicola was purified with the goal of assessing its effect on growth of malignant melanoma. Ammonium sulfate-sodium citrate fractionation and diethylaminoethyl cellulose-hydroxylapatite chromatography were used. The purified enzyme was shown to reduce plasma tyrosine levels when administered to normal C57BL x DBA/2 F1 mice. The plasma half-life value of the enzyme was found to be 6 to 7 hr. Unlike results reported with glutaminase and asparaginase preparations, the lactate dehydrogenase-elevating virus had no significant influence on plasma clearance of tyrosine phenol-lyase. The enzyme significantly inhibited growth of established B-16 melanoma tumors.

Animals↗
PubMedDate not supplied

Characterization of DNA adducts derived from (+/- )-trans-3,4-dihydroxy-anti-1,2-epoxy-1,2,3,4- tetrahydrodibenz[a,j]anthracene and (+/- )-7-methyl-trans-3,4-dihydroxy- anti-1,2-epoxy-1,2,3,4-tetrahydrodibenz[a,j]anthracene.

Structural characterizations of the DNA adducts derived from reaction of the racemic bay region anti-diol epoxides of dibenz[a,j]anthracene and 7-methyldibenz[a,j]anthracene with calf thymus DNA are presented. Quantities of adducts necessary for spectroscopic characterization were obtained from reactions of the respective diol epoxides with individual deoxyribonucleotides. Both hydrocarbon diol epoxides showed similar adduct profiles upon reaction with calf thymus DNA in vitro which were composed mainly of three deoxyguanosine and four deoxyadenosine adducts. No significant modification of pyrimidine bases in DNA was detected with either of the diol epoxides. Approximately 3 times more deoxyguanosine than deoxyadenosine residues in the DNA were found to be modified by both diol epoxides. The DNA reactions showed very similar stereo- and enantioselectivities with both diol epoxides. The stereochemistries of addition of the purine bases to the diol epoxides were determined from analysis of the NMR spectra of individual adducts. The predominant adducts formed were products of trans addition of the exocyclic amino group of purines to the diol epoxides. The enantiomeric nature of the various adducts was determined from reaction of the individual deoxyribonucleotides with the pure (+)-anti-diol epoxide of dibenz[a,j]anthracene. The major deoxyguanosine and deoxyadenosine adducts from reactions with DNA were found to arise from the (+)-enantiomer of both hydrocarbon diol epoxides. The high reactivities of both diol epoxides (24-38%) with DNA in solution are consistent with the high tumor-initiating activity exhibited by the diol epoxide of dibenz[a,j]anthracene relative to the parent hydrocarbon.

Animals↗
PubMedDate not supplied

Characterization of covalently modified deoxyribonucleosides formed from dibenz[a,j]anthracene in primary cultures of mouse keratinocytes.

Identification of various deoxyribonucleoside adducts formed in primary cultures of mouse keratinocytes exposed to dibenz[a,j]anthracene (DB[a,j]A) is presented. A preliminary analysis of the DNA adducts formed from 7-methyldibenz[a,j]anthracene (7MeDB[a,j]A) also is presented. Cultures of keratinocytes obtained from dorsal skins of female SENCAR mice were exposed to 0.5 microgram of tritium-labeled hydrocarbons/mL of medium for 24 h. The total DNA binding was 2.23 +/- 0.54 and 5.28 +/- 0.97 pmol of hydrocarbon/mg of DNA for DB[a,j]A and 7MeDB[a,j]A, respectively. These binding values represented the radioactivity associated with the modified deoxyribonucleosides separated from the normal deoxyribonucleosides on Sephadex LH-20 columns following enzymatic digestion of isolated DNA. Treatment of keratinocytes with DB[a,j]A produced adduct peaks corresponding to marker adducts derived from trans addition of both deoxyguanosine as well as deoxyadenosine residues to the (+) enantiomer of the anti-diol epoxide where the deoxyadenosine adducts were predominant. In addition, DNA adduct peaks corresponding to markers of trans and cis addition, respectively, of deoxyguanosine and deoxyadenosine to the (+)-syn-diol epoxide were also noted in these chromatograms. A major DNA adduct in cells exposed to DB[a,j]A was tentatively identified as resulting from the addition of deoxyadenosine to DB[a,j]A-5,6-oxide. Several other later eluting DNA adduct peaks, not corresponding to any of the marker adducts, were also present in these chromatograms. In comparison, when cells were exposed to the more biologically potent 7-methyl analogue, at least 12 DNA adduct peaks were consistently observed in HPLC chromatograms.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Comparative metabolism of dibenz[a,j]anthracene and 7-methyldibenz[a,j]anthracene in primary cultures of mouse keratinocytes.

The identification of several metabolites formed from dibenz[aj]anthracene (DB[aj]A) and 7-methyldibenz[aj]anthracene (7MeDB[aj]A) in primary cultures of mouse keratinocytes is presented. The metabolites were analyzed by coelution with known synthetic standards using high-pressure liquid chromatography. The metabolite identifications were further facilitated by comparisons of fluorescence excitation and emission spectra obtained for isolated metabolites with those for the synthetic standards. Both DB[aj]A and its 7-methyl analog were converted by mouse keratinocytes to the corresponding 3,4- as well as 5,6-dihydrodiols. The 5,6-dihydrodiol of DB[aj]A was the major intracellular metabolite found at all time points up to 24 h. By 48 h, the relative proportion of both intracellular dihydrodiols had decreased, and they were found in approximately equal proportions. In contrast, 7MeDB[aj]A-3,4- dihydrodiol was the major intracellular metabolite of 7MeDB[aj]A at all time points examined up to 48 h. The decreased intracellular retention of DB[aj]A-3,4-dihydrodiol was due, in part, to glucuronide conjugation and subsequent excretion of this metabolite. In this regard, both the 3,4- as well as the 5,6-dihydrodiols of DB[aj]A were found as glucuronides in the extracellular medium, whereas no such conjugates were detected extracellularly in cultures exposed to the 7-methyl derivative. The chromatographic profiles of cell- and medium-associated metabolites from both hydrocarbons also exhibited several other metabolite peaks that remain to be identified. The observed differences in dihydrodiol metabolism by mouse keratinocytes could explain, in part, the greater biological activity of 7MeDB[aj]A relative to DB[aj]A.

Animals↗
PubMedDate not supplied

Construction of Escherichia coli vectors containing deoxyadenosine and deoxyguanosine adducts from (+)-anti-dibenz[a,j]anthracene diol epoxide at a defined site.

Dibenz[a,j]anthracene (DB[a,j]A) is a carcinogenic polycylic aromatic hydrocarbon, which is metabolically activated through the formation of bay region diol epoxides. Site-specifically modified M13mp19-based vectors containing a single (+)-anti-dibenz[a,j] anthracene diol epoxide [(+)-anti-DB[a,j[A-DE]-deoxyguanosine (dGuo) or -deoxyadenosine (dAdo) adduct were constructed. Four-base oligonucleotides, 5'-HOTGCA-3' and 5'-HOCATG-3', corresponding to the central four base pairs in the PstI and SphI restriction endonuclease sites, respectively, in the multiple cloning region of M13mp19, were reacted in solution with (+/-)-anti-DB[a,j]A-DE. The resulting adducted oligonucleotides were separated and purified using reverse-phase HPLC. Several different singly adducted oligonucleotides were isolated, consisting of the various cis and trans addition products of the (+) and (-) enantiomers of the diol epoxide bound to dGuo or dAdo in the oligonucleotides. 5'-HOTGCA-3' containing the (+)-anti-DB[a,j]A-trans-N2-dGuo adduct [T(DB[a,j]A-N2)GCA] and 5'-HOCATG-3' containing the (+)-anti-DB[a,j]A-trans-N6-dAdo adduct [C(DB[a,j]A-N6)ATG) were selected for subsequent ligation into M13mp19 vectors that had been constructed with a corresponding four base gap in the minus strand. Both unmodified and adducted oligonucleotides were successfully ligated into the M13mp19 vectors, [yields: unmodified -TGCA-M13mp19 (approximately 32%) and -CATG- M13mp19 (approximately 42%); adducted T(DB[a,j]A-N2)GCA-M13mp19 (approximately 13%) and C(DB[a,j]A-N6)ATG-M13mp19 (approximately 12%)]. The dAdo adduct-containing vector was characterized. The presence of a dAdo-DNA adduct at the recognition site of SphI inhibited restriction by SphI.(ABSTRACT TRUNCATED AT 250 WORDS)

Benz(a)Anthracenes↗
PubMedDate not supplied

Inhibition and inactivation of murine hepatic ethoxy- and pentoxyresorufin O-dealkylase by naturally occurring coumarins.

The present study was designed to evaluate the effects of a series of natural coumarins on ethoxyresorufin O-dealkylase (EROD) and pentoxyresorufin O-dealkylase (PROD) activities in vitro using hepatic tissues from SENCAR mice. Fifteen different coumarins were examined for potential modulating activities. Several naturally occurring coumarins, found in the human diet, were effective inhibitors of hepatic EROD activity in vitro, including coriandrin, bergamottin, isoimperatorin, and ostruthin. Notably, coriandrin and bergamottin were approximately as potent as 7,8-benzoflavone, a relatively selective inhibitor of cytochrome P450 1A1. Several naturally occurring coumarins were also potent inhibitors of hepatic PROD activity, including imperatorin, bergamottin, isopimpinellin, and angelicin. Kinetic studies of the type of inhibition revealed that these compounds inhibited hepatic EROD and PROD activity by a variety of modes rather than by a uniform one. Furthermore, experiments using a two-stage incubation assay revealed that coriandrin, imperatorin, ostruthin, and several other natural coumarins inactivated hepatic EROD activity (i.e., predominantly cytochrome P450 1A1-mediated) and that isopimpinellin inactivated hepatic PROD activity (i.e., predominantly cytochrome P450 2B1-mediated). Finally, the results indicate that some coumarins had selective inhibitory effects for EROD vs PROD and preliminary analyses suggested a possible structural basis for the observed differences. The current data suggest that certain naturally occurring coumarins, to which humans are exposed in the diet, are potent modulators of cytochrome P450. Furthermore, these compounds may be capable of influencing the metabolic activation of other xenobiotics, including chemical carcinogens.

Animals↗
PubMedDate not supplied

Metabolism of 7,12-dimethylbenz[a]anthracene in mouse skin homogenates analyzed with high-pressure liquid chromatography.

The metabolism of 7,12-dimethylbenz[a]anthracene (DMBA) in epidermal homogenates from 3-methylcholanthrene-pretreated mice was analyzed with high-pressure liquid chromatography. Metabolism was undetectable in the absence of pretreatment. Specific activities in epidermal homogenates from pretreated mice were found to be approximately 100 to 1000 times lower than those observed in comparable incubations containing hepatic microsomes from MC-pretreated rats. The major metabolite formed was identified as 7-hydroxymethyl-12-methylbenz[a]anthracene. Each of the known hydroxymethyl metabolites also was present in detectable quantities. The K-region diol was not measurably present in incubations with mouse skin homogenates or rat liver microsomes from MC-pretreated animals. 7,8-Benzoflavone, 5,6-benzoflavone, and 17-beta-estradiol were found to be potent inhibitors of the metabolic transformation of DMBA by epidermal homogenates in vitro, whereas butylated hydroxytoluene and 1,1,1-trichloro-2,3-propene oxide had little effect on or enhanced metabolite formation from DMBA in vitro.

9,10-Dimethyl-1,2-benzanthracene↗