PubMed Health⌕ Search

Biomedical subjects

C C Duke

Publications and source records attributed to C C Duke.

31 records · Page 2Linked to original sources
PubMed1990

Photochemical studies on the anti-inflammatory drug diclofenac.

Irradiation with UVA light of the anti-inflammatory drug diclofenac [2-(2,6-dichloroanilino)phenylacetic acid] in aqueous buffer or methanol solution leads to sequential loss of both chlorine substituents and ring closure to carbazole-1-acetic acid as the major product. Minor products result from substitution by the solvent. The photosensitizing properties of diclofenac and its major photoproduct were tested with singlet oxygen substrates and in the free radical polymerization of acrylamide. Although the major carbazole product is a weakly phototoxic agent, able to generate singlet oxygen more efficiently than diclofenac, the free radical photodechlorination process is postulated as the probable initiation step of in vivo photosensitivity responses.

Diclofenac↗
PubMed1990

The metabolism of the carcinogen dibenz[a,j]acridine in isolated rat hepatocytes and in vivo in rats.

1. 3H-Dibenz[a,j]acridine (DBAJAC) metabolism occurred readily in vitro in incubations with hepatocytes from phenobarbital-pretreated, 3-methylcholanthrene-pretreated and untreated rats, with the formation of water-soluble conjugates and unconjugated metabolites. 2. For incubations of 3H-DBAJAC with hepatocytes the major organic solvent-soluble metabolites found with and without beta-glucuronidase/arylsulphatase hydrolysis were the phenols, 3-hydroxy-DBAJAC, and 4-hydroxy-DBAJAC, and the proposed proximate carcinogen, trans-3,4-dihydroxy-3,4-dihydro-DBAJAC. The latter comprised 34-66% of the total organic solvent-soluble metabolites. 3. In contrast to results previously reported for rat hepatic microsomes, the K-region 5,6-oxide, and its dihydrodiol were minor metabolites detected after hepatocyte incubations. 4. Faecal excretion accounted for the bulk of radioactivity after i.p. doses of 3H-DBAJAC (0.5 mg/kg), and i.v. doses (0.5 mg/kg) were rapidly excreted into the 6 h bile. The organic solvent-soluble fraction obtained after enzymic hydrolysis of bile (approximately 25% of excreted radioactivity) was subjected to h.p.l.c. It contained polar secondary oxidation products and virtually no 3,4-dihydrodiol. 5. Experiments conducted with greater hepatocyte densities (10(7) cells/ml) and longer incubation times showed increased extents of metabolism, DNA and protein binding of radioactivity which paralleled the extent of metabolism. Very considerable metabolism of the 3,4-dihydrodiol occurred by the end of the incubation period.

Acridines↗
PubMed1989

The mutagenicity of dibenz[a,j]acridine, some metabolites and other derivatives in bacteria and mammalian cells.

Dibenz[a,j]acridine (DBAJAC) was studied because of its close structural relationship with a number of important carcinogenic polycyclic and azaaromatic hydrocarbons. It was of particular relevance to examine the mutagenicity of known or proposed 'bay-region' metabolites, which may be proximate or ultimate carcinogenic derivatives of DBAJAC. Trans-1,2-, 3,4- and 5,6-dihydrodiols, the 4- and 6-phenols, the 5,6-oxide and N-oxide derivatives, and anti- and syn-3,4-diol 1,2-epoxides of DBAJAC were examined for their mutagenicity in Salmonella typhimurium TA98 and TA100 and in V79 Chinese hamster lung cells. Of all the compounds studied which require metabolic activation, the 3,4-dihydrodiol was the most active in both TA100 and in V79 cells. The activity of the 3,4-dihydrodiol enantiomers was also tested in strain TA100 where no difference was observed from that of the racemic mixture. In V79 cells only the 3R,4R-dihydrodiol was active, the activity being about three times that of the racemic material. Salmonella strains TA98 and TA100 also differed in their sensitivity towards DBAJAC dihydrodiols, the 1,2-isomer being of greatest activity in TA98. The most mutagenic compounds in both mammalian and bacterial cells were the 'bay-region' diol epoxides of DBAJAC which did not require metabolic activation by S9 mix. The anti-DBAJAC 3,4-diol 1,2-epoxide was more mutagenic than the syn form in V79, TA98 and TA100 cells. Overall these results suggest that the in vivo biological activity of DBAJAC metabolites is likely to reflect previous findings with other similar polycyclic aromatic hydrocarbons.

Acridines↗
PubMed1988

endo-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene-2-carboxylic acid, a superior resolving agent for the high-performance liquid chromatographic separation of enantiomers of hydroxylated derivatives of two azaaromatic hydrocarbons.

The high-performance liquid chromatographic (HPLC) separation of enantiomers of oxide and hydroxy derivatives of dibenz[a,j]acridine and 7-methylbenz[c]acridine was investigated on a chiral stationary phase chromatography column using commercially available columns. In most cases either poor or no separation of enantiomers was achieved. Normal-phase separation of diastereoisomeric ester derivatives of the hydroxy compounds, prepared from commercially available (-)-menthoxyacetic acid or (+)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetic acid, was investigated. No separation of the diastereoisomeric esters of trans-3,4-dihydroxy-3,4-dihydrodibenz[a,j]acridine was observed. However, diastereoisomeric esters prepared from (+)-endo-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene-2-carboxyl ic acid [(+)-HCA] were easily separated. Using the three chiral acids, diastereoisomers were prepared from sixteen hydroxy derivatives of dibenz[a,j]acridine and 7-methylbenz[c]acridine. (+)-HCA esters gave good to excellent HPLC separations which were superior to those achieved using other chiral acids in most cases. The enantiomeric composition of trans-3,4-dihydroxy-3,4-dihydrodibenz[a,j]acridine formed as a major rodent liver microsomal metabolite of dibenz[a,j]acridine was determined using (+)-HCA.

Acylation↗
PubMed1987

Dibenz [a,j]acridine: distributions of metabolites formed by liver and lung microsomes from control and pretreated rats.

The structures of many dibenz[a,j]acridine (DBAJAC) metabolites formed in vitro in incubations with liver microsomes prepared from 3-methylcholanthrene-pretreated male Wistar rats have previously been determined; they were trans-DBAJAC-3,4-dihydrodiol, trans-DBAJAC-5,6-dihydrodiol, DBAJAC-5,6-oxide, 3-hydroxy-DBAJAC, 4-hydroxy-DBAJAC and several multiply oxidized secondary metabolites. Herein are reported [14-3H]DBAJAC metabolite distributions obtained by h.p.l.c. separation of products produced in incubations with liver and lung microsomes prepared from untreated, phenobarbital-pretreated and 3-methylcholanthrene-pretreated male Wistar rats. Liver microsomal metabolites were also quantitated in preparations from trans-stilbene oxide-pretreated rats. For all preparations trans-DBAJAC-3,4-dihydrodiol, the candidate proximate carcinogen according to the bay-region theory of carcinogenesis, was the major metabolite (30-40%) while DBAJAC-5,6-oxide and phenols were also quantitatively important. In incubations conducted in the presence of 3,3,3-trichloropropene-1,2-oxide (1.5 mM) formation of dihydrodiol was inhibited by about 85%. DBAJAC-N-oxide was also identified as a minor metabolite (approximately 1%) formed in incubations with phenobarbital-induced and control liver microsomes.

Acridines↗
PubMed1986

7-Methylbenz[c]acridine: mutagenicity of some of its metabolites and derivatives, and the identification of trans-7-methylbenz[c]-acridine-3,4-dihydrodiol as a microsomal metabolite.

The presence of the proposed proximate carcinogen, trans-3,4-dihydro-3,4-dihydroxy-7-methylbenz[c]acridine (7MBAC-3,4-DHD) among the liver microsomal metabolites of 7-methylbenz[c]acridine (7MBAC) has been demonstrated using gas chromatography mass spectrometry (GCMS) and by co-chromatography with synthetic standards on reverse and normal phase h.p.l.c. 7MBAC-3,4-DHD represented 2.2-3.4% of the total ethyl acetate-extractable metabolites formed from 7MBAC by liver microsomes prepared from untreated and induced rats. About 2.3-2.7% of metabolites formed by lung microsomes was identified as 7MBAC-3,4-DHD. Mutagenicity studies with 7MBAC-3,4-DHD have been carried out in bacterial and mammalian systems using S9 fractions derived from rats pre-treated with Aroclor and guinea pigs pre-treated with 3-methylcholanthrene. Comparative data with other 7MBAC derivatives are also reported. The 7MBAC-3,4-DHD and the analogous dihydro derivative of 7MBAC were the most potent mutagens of those compounds requiring metabolic activation. The data imply that the 3,4-dihydrodiol is metabolised to a bay region diol epoxide as the ultimate carcinogen. In support of this anti-1,2-epoxy-trans-3,4-dihydroxy-7-methyl-1,2,3,4- tetrahydrobenz[c]acridine was a potent mutagen in the Ames and V79 cell systems without activation. The syn-isomer was less active.

Acridines↗
PubMed1986

Dibenz[a,j]acridine metabolism: identification of in vitro products formed by liver microsomes from 3-methylcholanthrene-pretreated rats.

The metabolism of the carcinogenic pentacyclic azaaromatic compound, dibenz[a,j]acridine, has been examined in liver microsomal incubations using preparations from 3-methylcholanthrene-pretreated Wistar rats. Using authentic synthetic standards, u.v. spectroscopy and mass spectrometry, the following were proved to be metabolites: trans-5,6-dihydro-5,6-dihydroxydibenz[a,j]acridine, trans-3,4-dihydro-3,4-dihydroxydibenz[a,j]acridine, dibenz[a,j]acridine-5,6-oxide, 3-hydroxydibenz[a,j]acridine and 4-hydroxydibenz[a,j]acridine. The 3,4-dihydrodiol appeared to be the major metabolite. The secondary metabolites were also examined and evidence is presented for the additional formation of dibenz[a,j]acridine-5,6,8,9-dioxide, tetrols, diol epoxides and phenolic dihydrodiols.

Acridines↗
PubMed1986

High tumorigenicity of the 3,4-dihydrodiol of 7-methylbenz[c]acridine on mouse skin and in newborn mice.

The tumorigenicities of 7-methylbenz[c]acridine (7MB[c]ACR) and its five metabolically possible trans-dihydrodiols were determined in two mouse tumor models. In initiation-promotion studies on mouse skin, a single topical application of 0.15 to 0.75 mumol of compound was followed 9 days later by twice weekly applications of 12-O-tetradecanoylphorbol-13-acetate for 20 wk. Comparison of the average number of skin tumors per mouse indicated that 7MB[c]ACR 3,4-dihydrodiol, the metabolic precursor of a bay-region diol-epoxide, was 4- to 6-fold more active than the parent compound as a tumor initiator. The 1,2-, 5,6-, 8,9-, and 10,11-dihydrodiols of 7MB[c]ACR had no significant tumor-initiating activity at the doses tested. In newborn mice, a total dose of 0.35 mumol of compound was administered i.p. during the first 15 days of life, and tumorigenic activity was determined when the mice were 32 to 36 wk old. 7MB[c]ACR 3,4-dihydrodiol induced about 8-fold more pulmonary tumors per mouse and 9-fold more hepatic tumors per male mouse than the parent aza-substituted hydrocarbon. The other four dihydrodiols of 7MB[c]ACR had no significant tumorigenic activity. The high tumorigenic activity of 7MB[c]ACR 3,4-dihydrodiol in both tumor models suggests that a bay-region 3,4-diol-1,2-epoxide may be an ultimate carcinogenic metabolite of 7MB[c]ACR. 7MB[c]ACR was at least 5-fold more active as a tumor initiator on mouse skin than was the unsubstituted aza-aromatic compound, benz[c]acridine. This latter result indicates that substitution of a methyl group at position 7 of benz[c]acridine leads to enhanced tumor-initiating activity, as has been previously demonstrated for benz[a]anthracene and its 7-methyl derivative.

Acridines↗
PubMed1983

Metabolism of 7-methylbenz[c]acridine: comparison of rat liver and lung microsomal preparations and identification of some minor metabolites.

The metabolism of the carcinogenic polycyclic aza-aromatic compound, 7-methylbenz[c]acridine, has been studied in lung and liver microsomal preparations obtained from control and induced rats. Minor metabolites not previously identified included, trans-10,11-dihydro-10,11-dihydroxy-7-methylbenz[c]acridine, trans-1,2-dihydro-1,2-dihydroxy-7-methylbenz[c]acridine, 7-methylbenz[c]acridine-5,6-oxide and 7-hydroxymethylbenz[c]acridine-5,6-oxide. Metabolite profiles from liver microsomes showed 7-hydroxymethylbenz[c]acridine, trans-8,9-diydro-8,9-dihydroxy-7-methylbenz[c]acridine, 7-methylbenz[c]acridine-5,6-oxide and phenols to be major products. Metabolite distributions obtained with lung microsomes were very similar although activities were much lower than those of liver microsomes prepared from the same animals.

Acridines↗
PubMedDate not supplied

Stereochemistry of the major rodent liver microsomal metabolites of thecarcinogen dibenz[a,j]acridine.

The major metabolites of the carcinogen dibenz[a,j]acridine formed in rodent liver microsomal preparations were trans-3,4-dihydroxy-3,4-dihydrodibenz[a,j]acridine (DBAJAC-3,4-DHD) and dibenz[a,j]acridine 5,6-oxide (DBAJAC 5,6-oxide) [Gill et al. (1987) Carcinogenesis 8, 425-431]. The enantiomers of DBAJAC-3,4-DHD were prepared from the separable diastereoisomeric esters with (+)-endo-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene-2-carboxyl ic acid (HCA). The absolute configuration of trans-3(R),4(R)-dihydroxy-1,2,3,4-tetrahydrodibenz[a,j]acridine was assigned by conversion to the bis[p-(dimethylamino)benzoate] and examination of the exciton coupling in its circular dichroic (CD) spectrum. The 3(R),4(R)-tetrahydrodiol was converted to DBAJAC-3(R),4(R)-DHD. The enantiomers of DBAJAC 5,6-oxide were partially resolved by chiral stationary-phase chromatography, and subsequent methoxide attack afforded two enantiomerically enriched isomeric ethers from each fraction. The structures of the two ethers from each enantiomer were determined, and from their 1H NMR spin-spin coupling between the H5 and H6 signals and the CD spectra of the ethers, the absolute configuration of the ethers, and hence the 5,6-oxides, was determined. The enantiomeric composition of the 3,4-dihydrodiol and 5,6-oxide formed as microsomal metabolites of rat liver preparations was 69% 3R,4R and 81% 5R,6S, respectively. When rats were pretreated with 3-methylcholanthrene (MC), these percentages were 70% and 5%, indicating a reversed stereochemical preference for oxide formation in the MC-induced preparation. Results are also presented for phenobarbitone-induced rat liver and mouse liver preparations.

Acridines↗
PubMedDate not supplied

Solvolysis of the bay-region diol epoxides of 7-methylbenz[c]acridine in aqueous solution and effect of DNA.

The hydrolysis of the bay-region syn- and anti-diol epoxides of 7-methylbenz[c]acridine (7MBAC) has been studied in aqueous solution. The rates of reaction have been measured at low ionic strength in the absence and presence of DNA, as a function of pH and temperature, by spectrophotometry and high-pressure liquid chromatography. The major products are the corresponding tetrols, but the syn diastereomer also undergoes rearrangement to a keto diol. The hydrolysis reaction is catalyzed by both acid and DNA and conforms to a mechanism in which a physical association complex is formed between diol epoxide and DNA, followed by two parallel pathways in which the diol epoxide either is hydrolyzed or becomes covalently bound to the DNA. The rate constants are significantly lower than the corresponding ones for the diol epoxides of benzo[a]pyrene. However, the extent of covalent binding of 7MBAC diol epoxides to DNA was found to be 12-30%, depending on the pH of reaction, values that are 2-3 times greater than for the benzo[a]pyrene diol epoxides reacted under the same conditions of low ionic strength. The very small changes (2 nm) in spectroscopic characteristics observed for the covalently bound adduct as compared to the free tetrol suggest that the binding occurs with little intercalation of the compound between the base pairs of DNA.

Acridines↗
PubMedDate not supplied

Stereochemistry of the major rat liver microsomal metabolites of the carcinogen 7-methylbenz[c]acridine.

The major metabolites of the carcinogen 7-methylbenz[c]acridine (7MBAC), trans-5,6-dihydro-5,6-dihydroxy-7-methylbenz[c]acridine (7MBAC-5,6-DHD), and trans-8,9-dihydro-8,9-dihydroxy-7-methylbenz[c]acridine (7MBAC-8,9-DHD) were characterized as their enantiomers after separation of their bis-(+)-(1R,2S,4S)-endo-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5 -ene-2-carboxylic acid [(+)-HCA] esters and hydrolysis. The synthetic precursor, trans-3,4-dihydroxy-7-methyl-1,2,3,4-tetrahydrobenz[c]acridine (7MBAC-3,4-THD), was similarly separated into enantiomers, and the dihydrodiol trans-3(S),4(S)-dihydro-3,4-dihydroxy-7-methylbenz[c]acridine (7MBAC-3,4-DHD) was prepared from 7MBAC-3(S),4(S)-THD. Absolute configurations were assigned by the chiral exciton coupling of the bis-p-(dimethylamino)benzoate of 7MBAC-3(R),4(R)-THD, and by the semiempirical methods based on the biaryl chromophores of the enantiomers of 7MBAC-5,6-DHD and of the methanolysis products of the 5,6-oxide of 7MBAC which were resolved as their (+)-HCA esters. X-ray crystallography was used for 7MBAC-8(S),9(S)-DHD bis-(+)-HCA ester, and assignments were correlated with chiral exciton coupling of the bis-4-(dimethylamino)cinnamates of 7MBAC-5(R),6(R)-DHD and 7MBAC-8(S),9(S)-DHD. The stereochemical compositions of four metabolites (three dihydrodiols and 7MBAC-5,6-oxide) formed in incubations with rat liver microsomes from control and induced liver were determined by normal-phase separations of bis-(+)-HCA esters, and by chiral stationary-phase separation of the 5,6-oxide methanolysis products. The 3(R),4(R)-enantiomer of 7MBAC-3,4-dihydrodiol predominated, 74-98% enantiomeric purity, and purity for the oxide varied from about 71% 5(R),6(S)-oxide for control microsomes to about 28% 5(R),6(S)-oxide for liver microsomes obtained from 3-methylcholanthrene-pretreated rats.

Acridines↗