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O Ribeiro

Publications and source records attributed to O Ribeiro.

At least 19 recordsLinked to original sources
PubMed1987

Metabolic activation to a mutagen of 3-hydroxy-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene, a secondary metabolite of benzo[a]pyrene.

3-Hydroxy-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (3-OH-BP-7,8-diol) was isolated from arylsulfatase/beta-glucuronidase-treated bile of rats to which 3-hydroxybenzo[a]pyrene (3-OH-BP) has been administered. This triol was investigated for mutagenicity in Salmonella typhimurium (reversion to histidine prototrophy of strains TA 97, TA 98, TA 100 and TA 1537) and in V79 Chinese hamster cells (acquisition of resistance to 6-thioguanine). When no exogenous metabolizing system was added the triol was inactive, while 3-OH-BP showed weak mutagenic effects with all four bacterial strains. In the presence of NADPH-fortified postmitochondrial supernatant fraction (S9 mix) of liver homogenate from Aroclor 1254-treated rats, the mutagenicity of 3-OH-BP was potentiated, and the triol was activated to a mutagen(s). In the presence of S9 mix, the triol was 5-18 times more mutagenic than 3-OH-BP in strains TA 97, TA 100 and TA 1537, but both compounds showed similar mutagenic potencies with strain TA 98. These strain differences strongly suggest that the mutagenicity of 3-OH-BP in the S9 mix-mediated test was not exclusively due to metabolites of 3-OH-BP-7,8-diol. Trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol), like the triol, showed mutagenic effects only in the presence of S9 mix. Strain TA 1537 was reverted by the triol but not by the diol. In the other bacterial strains the diol was more mutagenic than the triol, the difference in potency being largest in strain TA 100 (2.5- to 10-fold, depending on the experimental conditions). In V79 cells, the diol was a potent mutagen, while the triol showed only very weak mutagenic effects. However the triol was more cytotoxic than the diol. High cytotoxicity of the triol was observed even in the absence of S9 mix. The results of the present study demonstrate that metabolites of 3-OH-BP-7,8-diol are biologically-active derivatives of benzo[a]pyrene. Comparison of the mutagenic effectiveness in different bacterial strains also reveals that metabolites of 3-OH-BP-7,8-diol and of BP-7,8-diol substantially differ in the kind of genetic alterations they evoke.

Animals↗
PubMed1986

Reactive intermediates from 3-hydroxybenzo[a]pyrene and its glucuronide.

3-Hydroxybenzo[a]pyrene (3-OH-BaP) is oxidized by the horseradish peroxidase/H2O2 system to benzo[a]pyrene-3,6-quinone. In the presence of N-acetylcysteine one other product is also formed. This was identified by its chemical, and u.v., mass and n.m.r. spectral properties as 6-(H-acetyl-cystein-S-yl)-3-hydroxybenzo[a]pyrene (6-NAc-cys-3-OH-BaP). Replacement of the N-acetylcysteine by glutathione leads to the formation of a 3-OH-BaP-glutathione adduct. Enzymic hydrolysis of benzo[a]pyrene-3-glucuronide in the presence of N-acetylcysteine yields, in addition to 3-OH-BaP, a product which co-chromatographs with 6-NAc-cys-3-OH-BaP and has identical chemical and spectral characteristics.

Acetylcysteine↗
PubMed1985

Secondary metabolites of benzo[a]pyrene: 3-hydroxy-trans-7,8-dihydro-7,8-dihydroxybenzo[a]pyrene, a biliary metabolite of 3-hydroxybenzo[a]pyrene in the rat.

Rats administered 3-hydroxybenzo[a]pyrene (50 mg/kg, i.p.), excrete via the bile metabolites which, after treatment with beta-glucuronidase and aryl sulphatase, yield, in addition to 3-hydroxybenzo[a]pyrene, 3-hydroxy-trans-7,8-dihydro-7,8-dihydroxybenzo[a]pyrene (3-OH-BP-7,8-diol) and a minor, highly labile, metabolite tentatively identified as 3,5-dihydroxybenzo[a]pyrene. These novel metabolites are readily isolated in a pure state via preparative layer chromatography. The structure of the 3-OH-BP-7,8-diol was revealed by its u.v., proton magnetic resonance and mass spectral properties. Its hydroxyl functions are in a predominantly quasi-diequatorial conformation.

Animals↗
PubMed1985

A comparative examination of the in vitro metabolism of five cyclopenta[a]phenanthrenes of varying carcinogenic potential.

Metabolites of 15,16-dihydrocyclopenta[a]phenanthren-17-one and its 1- and 12-methyl homologues (all non-carcinogens) along with those from the 11-methyl and 11,12-dimethyl-17-ketones (carcinogens), produced in vitro by hepatic microsomes from methylcholanthrene induced rats, were separated by reverse phase h.p.l.c. Identifications of individual metabolites were based upon elution times, u.v. spectra, and in some cases by mass spectrometry, circular dichroism, and identity with synthetic derivatives. All five compounds were biologically oxidised at their terminal A and D rings to yield 1,2-dihydrodiols and 15- and 16- ols; with the exception of the 1-methyl compound, all also gave similar amounts of 3,4-dihydrodiols. The 1-methyl compound by contrast failed to produce this metabolite, furnishing instead the 4-phenol and five other, probably related phenolic derivatives. Previous work has established that for the 11-methyl-17-ketone, the 3,4-dihydrodiol is the proximate carcinogen. Thus, whereas lack of biological activity with the 1-methyl compound can be ascribed to its failure to produce a 3,4-dihydrodiol, in the case of the unsubstituted parent ketone and its 12-methyl derivative other determining factors must come into play.

Animals↗
PubMed1985

Metabolism and enterohepatic circulation of benzo(a)pyrene-4,5-epoxide in the rat.

After i.v. administration of 3H-benzo(a)pyrene-4,5-epoxide (32.5 mumol/kg) to rats, 76% of the 3H appeared in bile within 3 h. The glutathione conjugate of benzo(a)pyrene-4,5-epoxide was the major biliary metabolite (33% of dose), together with a glucuronic acid conjugate of benzo(a)pyrene-4,5-diol (18%) and an unidentified metabolite (10%). The glutathione and glucuronic acid conjugates both undergo extensive enterohepatic circulation. Thus, following the intraduodenal administration of the 3H-labelled conjugates, 26% of the radioactivity was excreted in the bile after 24 h in the case of the glutathione derivative, and 40% in the case of the glucuronide. The benzo(a)pyrene-4,5-diol glucuronide, on enterohepatic circulation, appears in the bile in the same form as the conjugate administered with no evidence of further metabolism of the polycyclic hydrocarbon moiety. The glutathione conjugate of benzo(a)pyrene-4,5-epoxide, on recirculation, is reexcreted in bile as one unidentified metabolite, which is susceptible to the action of arylsulphatase.

Animals↗
PubMed1981

The metabolic activation of benz[alpha]anthracene in three biological systems.

The 3,4- and 8,9-dihydrodiols of benz[alpha]anthracene (BA) are formed as metabolites of the parent hydrocarbon by rat-liver microsomes, by mouse skin and by hamster embryo cells. In incubations with rat-liver microsomal fractions, only small amounts of the 3,4-dihydrodiol of BA were detected relative to other dihydrodiol metabolites and only small amounts of BA-deoxyribonucleoside adducts derived from the related diol-epoxide, t-3, r-4-dihydroxy-t-1,2-oxy-1,2,3,4-tetrahydrobenz[alpha]anthracene (anti-BA-3,4-diol 1,2-oxide), were detected relative to adducts derived from r-8,t-9-dihydroxy-t-10,11-oxy-8,9,10,11-tetrahydrobenz[alpha]anthracene (anti-BA-8,9-diol 10,11-oxide). However, in studies with mouse skin and hamster embryo cells, larger amounts of free 3,4-dihydrodiol were detected and a larger proportion of the hydrocarbon-deoxyribonucleoside adducts resulted from the reaction of anti-BA-3,4-diol 1,2-oxide with DNA.

Animals↗
PubMed1981

The metabolic and activation of dibenz[a,c]anthracene.

In rat liver microsomal preparations, the 10,11-dihydrodiol of dibenz[a,c]anthracene (DBA) is metabolized to r-10,t-11-dihydroxy-t-12,13-oxy-10,11,12,13-tetrahydrodibenz[a,c]anthracene (anti-DBA 10,11-diol 12,13-oxide), the anti isomer of a non-bay-region diol-epoxide of DBA. When 3H-labelled DBA or trans-10,11-dihydro-10,11-dihydroxydibenz[a,c]anthracene were metabolized in this system in the presence of DNA or when 3H-labelled DBA was added to primary cultures of hamster embryo cells, covalent reactions of hydrocarbon metabolites with DNA occurred. The chromatographic characteristics of the radioactive hydrocarbon-deoxyribonucleoside adducts formed in these reactions were examined using Sephadex LH20 column chromatography and high pressure liquid chromatography. The results showed that whilst some of the radioactive hydrocarbon-deoxyribonucleoside adducts formed were indistinguishable from adducts that were formed when anti-DBA 10,11-diol 12,13-oxide reacted with DNA, other, unidentified adducts, which did not apparently arise from reactions of this diol-epoxide with DNA, were also present. Hydrocarbon-nucleoside adducts were not detected in hydrolysates of nucleic acids that were isolated from mouse skin that had been treated in vivo with DBA.

Animals↗
PubMed1980

The metabolic activation of benz[a]anthracene in hamster embryo cells: evidence that diol-epoxides react with guanosine, deoxyguanosine and adenosine in nucleic acids.

The principal nucleoside-hydrocarbon adducts present in hydrolysates of RNA and DNA isolated from hamster embryo cells treated with benz[a]anthracene (BA) were examined by chromatography on Sephadex LH 20 and by high pressure liquid chromatography (HPLC) on Spherisorb 5 ODS. The results extend the previous finding that a non-'bay-region' diol-epoxide, anti-BA-8,9-diol 10,11-oxide (r-8,t-9-dihydroxy-t-10,11-oxy-8,9,10,11-tetrahydrobenz[a] anthracene) is involved in the binding of BA to cellular nucleic acids and show that this diol-epoxide most probably reacts with guanosine and adenosine in RNA and with deoxyguanosine in DNA. The results also show that a 'bay-region' diol-epoxide anti-BA-3,4-diol 1,2-oxide (t-3,-4-dihydroxy-t-1,2-oxy-1,2,3,4-tetrahydrobenz[a]anthracene, which is thought to be involved in the binding of benz[a]anthracene, which is thought to be involved in the binding of benz[a]anthracene to DNA in some situations, reacts mainly with deoxyguanosine.

Adenosine↗
PubMed1980

Additional evidence for the involvement of the 3,4-diol 1,2-oxides in the metabolic activation of 7,12-dimethylbenz[a]anthracene in mouse skin.

The role of vicinal diol-epoxides in the metabolic activation of 7,12-dimethylbenz[a]anthracene to intermediates that react with nucleic acids was investigated using Sephadex LH-20 column chromatography and high pressure liquid chromatography. The results show that some of the hydrocarbon-DNA products formed in mouse skin treated in vivo with 7,12-dimethylbenz[a]anthracene arise from the reaction of DNA with 3,4-dihydro-3,4-dihydroxy-7,12-dimethylbenz[a]anthracene 1,2-oxides which, on the basis of this and other evidence, appears to be a biologically-active metabolite of 7,12-dimethylbenz[a]anthracene. However, since other nucleic acid-hydrocarbon adducts were also present that have not been identified as resulting from the reaction of the 3,4-diol 1,2-oxides with DNA, other mechanisms may also be involved in the metabolic activation of 7,12-dimethylbenz[a]anthracene in mouse skin.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

The involvement of a non-'bay-region' diol-epoxide in the metabolic activation of benza[a]anthracene in hamster embryo cells.

The major hydrocarbon-nucleoside adduct present in hydrolysates of DNA from hamster embryo cells that had been treated with 3H-labelled benz[a]anthracene in culture has been examined by chromatography on Sephadex LH-20 columns and by high-pressure liquid chromatography. The results show that this adduct most probably arises from r-8,t-9-hydroxy-t-10,11-oxy-8,9,10,11-tetrahydrobenz[a]anthracene (anti-BA-8,9.-diol 10,11-oxide). On the basis of this and other evidence, this non-bay-region diol-epoxide appears to be a reactive intermediate involved in the metabolic activation of benz[a]anthracene.

Animals↗
PubMed1980

The metabolism of the 10,11-dihydrodiol of benz[a]-anthracene to a vicinal diol-epoxide that is not involved in metabolic activation.

Benz[a]anthracene-10,11-diol, a major metabolite of benz[a]anthracene, is metabolized by a rat-liver microsomal system to form anti-BA-10,11-diol 8, 9-oxide (t-10,r-11-dihydroxy-t-8,9-oxy-8,9,10,11 -tetrahydrobenz[a]anthracene) and, to a lesser extent, syn-BA-10,11-diol 8,9-oxide (t-10,r-11-dihydroxy-c-8,9-oxy-8,9,10,11-tetrahydrobenz[a] anthracene). However, when benz[a]anthracene is incubated with DNA in a rat-liver microsomal system, anti-BA-10,11-diol 8,9-oxide does not contribute to the covalent binding of this hydrocarbon to DNA.

Animals↗
PubMed1980

The enzyme-catalysed conversion of anti-benzo[a]pyrene-7,8-diol 9,10-oxide into a glutathione conjugate.

Anti-BP-7,8-diol 9,10-oxide (r-7,t-8-dihydroxy-t-9, 10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene) was converted in the presence of a rat-liver supernatant fraction and glutathione into a water-soluble metabolite that was identified as a glutathione conjugate. The formation of the glutathione conjugate appears to be catalysed by glutathione S-transferases, present in the rat-liver supernatant, because the amount of conjugate formed was reduced considerably when anti-BP-7,8-diol 9,10-oxide was incubated with glutathione either in the absence of the supernatant fraction or in the presence of heat-denatured supernatant fraction.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1980

Metabolic activation of benz[a]anthracene in hamster embryo cells: the structure of a guanosine-anti-BA-8,9-diol 10,11-oxide adduct.

The structures of two guanosine-hydrocarbon adducts prepared from polyG that had been incubated with anti-BA-8,9-diol 10,11-oxide (r-8,t-9-dihydroxy-t-10,11-oxy-8,9,10,11-tetrahydrobenz[a]anthracene) were investigated by examining their H-n.m.r. spectra, their pK values before and after treatment with nitrous acid and their stabilities in 1M KOH. The data show that both of the adducts were formed by reaction between the exocyclic amino group of guanine and the 11-position of the diolepoxide. One of these adducts is indistinguishable from an adduct isolated from hamster embryo cells that had been treated with benz[a]anthracene and that may contribute to the biological activity of this weak carcinogen.

Animals↗