RESUMEN
The tumorigenic activities of benzo[a]pyrene (BP) and 6-fluorobenzo[a]pyrene (6-F-BP) were compared to determine whether an unsubstituted 6-position is important for the carcinogenic effect of BP. Highly purified samples of 6-F-BP and BP had similar activities for the induction of lung adenomas in Swiss Webster mice treated before weaning. The 6-fluoro derivative, however, had about one-half as much activity as BP for the initiation of skin papillomas in CD-1 mice. Similarly, 6-F-BP (approximately equal to 90% purity) had about one-half the activity of BP for the induction of skin tumors in C57BL/6J mice given repetitive treatments of the hydrocarbons and for the induction of sarcomas in C3H/fCum mice given a single sc injection. 6-F-BP (approximately equal to 90% purity) had activity similar to that of BP for induction of sarcomas at the sc injection site in Fischer 344 rats. These results and related data indicate the need for detailed metabolic studies whenever fluorine substitution is used as a probe to assess the role of the unsubstituted position in the carcinogenicity of the parent compound.
Asunto(s)
Benzopirenos/toxicidad , Carcinógenos/toxicidad , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Pulmonares/inducido químicamente , Papiloma/inducido químicamente , Sarcoma Experimental/inducido químicamente , Neoplasias Cutáneas/inducido químicamente , Animales , Benzo(a)pireno , Femenino , Neoplasias Hepáticas Experimentales/patología , Neoplasias Pulmonares/patología , Masculino , Ratones , Neoplasias Experimentales/patología , Papiloma/patología , Ratas , Sarcoma Experimental/patología , Factores Sexuales , Neoplasias Cutáneas/patología , Especificidad de la EspecieRESUMEN
Benzo(a)pyrene (BP), 2-hydroxybenzo(a)pyrene (2-HOBP), and 6-hydroxybenzo(a)pyrene (6-HOBP) were tested for tumorigenicity by i.p. injection into newborn mice. The mice were treated sequentially with 200, 400, and 800 nmol of compound on the first, eighth and fifteenth day of life, and the animals were killed at 24 weeks of age. Treatment with 2-HOBP caused about 4-fold more pulmonary tumors than BP, while 6-HOBP had little or no tumorigenic activity. Newborn mice treated with 2-HOBP, BP, and 6-HOBP had a 98, 81, and 11% incidence of pulmonary adenomas with an average of 24, 6.4, and 0.11 adenomas per mouse, respectively. In the control group, 7.5% of the animals had pulmonary adenomas with an average of 0.08 adenoma per mouse. When 25, 50, or 100 nmol of BP or 2-HOBP was applied to mouse skin once every 2 weeks for 60 weeks, both compounds had about the same carcinogenic activity. These results demonstrate the importance of evaluating the carcinogenic potential of chemicals in more than one tumor system. BP and 2-HOBP were tested for mutagenicity towards two strains of Salmonella typhimurium and towards Chinese hamster V79 cells in the presence of hepatic microsomes from rats pretreated with Aroclor 1254. The products formed during the metabolism of 2-HOBP or BP by liver microsomes had significant mutagenic activity.
Asunto(s)
Adenoma/inducido químicamente , Animales Recién Nacidos , Benzopirenos/toxicidad , Carcinógenos , Neoplasias Pulmonares/inducido químicamente , Animales , Células Cultivadas , Cricetinae , Cricetulus , Inyecciones Intraperitoneales , Ratones , Ratones Endogámicos C57BL , Mutágenos , Neoplasias Experimentales/inducido químicamente , Salmonella typhimurium/efectos de los fármacos , Piel/efectos de los fármacos , Neoplasias Cutáneas/inducido químicamenteRESUMEN
The tumor-initiating activities of chrysene and the three metabolically possible trans-dihydrodiols at the 1,2-, 3,4-, and 5,6-positions of chyrsene were determined on the skin of female CD-1 mice. A single topical application of 0.4, 1.25, or 4.0 mumol of each compound was followed 7 days later by twice-weekly applications of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate for 25 weeks. The most potent tumor initiator was chrysene 1,2-dihydrodiol, which had approximately twice the tumorigenic activity of the parent hydrocarbon chrysene at all doses tested. Chrysene 3,4-dihydrodiol and chrysene 5,6-dihydrodiol had no significant tumorigenic activity. 1,2-Dihydroxy-1,2,3,4-tetrahydrochrysene, a compound related to chrysene 1,2-dihydrodiol but with the conjugated nonaromatic double bond removed from the 3,4-position of the molecule, had less than 25% of the tumorigenic activity of chrysene 1,2-dihydrodiol. These results indicate that chrysene 1,2-dihydrodiol is a proximate carcinogenic metabolite of chrysene and that a chrysene 1,2-diol-3,4-epoxide, in which the epoxide group forms part of the bay region in the molecule, is a likely candidate as an ultimate carcinogenic metabolite of chrysene.
Asunto(s)
Carcinógenos , Crisenos/metabolismo , Fenantrenos/metabolismo , Neoplasias Cutáneas/inducido químicamente , Animales , Fenómenos Químicos , Química , Crisenos/toxicidad , Femenino , Ratones , Neoplasias Experimentales/inducido químicamenteRESUMEN
A variety of radioactive analogs of adenine and adenosine were incubated with guinea pig cerebral cortical slices. Neither 1,N6-etheno[14C] adenosine nor 1,N6-etheno[14C] adenine were significantly incorporated into intracellular nucleotides. 2-chloro[8-3H] adenine was incorporated, but at a very low rate and conclusive evidence for the formation of intracellular radioactive 2-chloro-cyclic AMP was not obtained. N6-Benzyl[14C] adenosine was converted only to intracellular monophosphates and significant formation of radioactive N6-benzylcyclic AMP was not detected during a subsequent incubation. 2'-Deoxy-[8-14C] adenosine was converted to both intracellular radioactive 2'-deoxy-adenine nucleotides and radioactive adenine nucleotides. Stimulation of these labeled slices with a variety of agents resulted in formation of both radioactive 2'-deoxycyclic AMP and cyclic AMP. Investigation of the effect of various other compounds on uptake of adenine or adenosine suggested that certain other adenosine analogs might serve as precursors of abnormal cyclic nucleotides in intact cells.
Asunto(s)
Adenina/análogos & derivados , Adenosina/análogos & derivados , Corteza Cerebral/metabolismo , AMP Cíclico/análogos & derivados , Adenina/metabolismo , Nucleótidos de Adenina/biosíntesis , Adenosina/metabolismo , Adenosina Monofosfato/biosíntesis , Animales , Corteza Cerebral/efectos de los fármacos , AMP Cíclico/biosíntesis , Desoxiadenosinas/metabolismo , Cobayas , Técnicas In Vitro , Masculino , Veratridina/farmacologíaAsunto(s)
Benzopirenos/toxicidad , Dihidroxidihidrobenzopirenos , Fibrosarcoma/inducido químicamente , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido , Animales , Benzopirenos/metabolismo , Biotransformación , Evaluación Preclínica de Medicamentos , Compuestos Epoxi/metabolismo , Compuestos Epoxi/toxicidad , Masculino , Ratones , Ratones Endogámicos C3H , Sarcoma Experimental/inducido químicamente , Relación Estructura-ActividadAsunto(s)
Benzopirenos/toxicidad , Neoplasias Cutáneas/inducido químicamente , Animales , Benzopirenos/metabolismo , Carcinoma de Células Escamosas/inducido químicamente , Femenino , Isomerismo , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales/inducido químicamente , Fenoles/toxicidad , Relación Estructura-ActividadAsunto(s)
Carcinógenos , Crisenos/toxicidad , Compuestos Epoxi/toxicidad , Éteres Cíclicos/toxicidad , Mutágenos , Fenantrenos/toxicidad , Animales , Crisenos/metabolismo , Cricetinae , Epóxido Hidrolasas/metabolismo , Femenino , Técnicas In Vitro , Masculino , Ratones , Neoplasias Experimentales/inducido químicamente , Fenantrenos/metabolismo , Ratas , Salmonella typhimurium/efectos de los fármacos , Neoplasias Cutáneas/inducido químicamente , Relación Estructura-ActividadRESUMEN
In order to study the biological effects of (+)- and (-)-benzo[a]pyrene 4,5-oxide, a synthesis of these molecules has been developed based on the resolution of (+/-)-cis-4,5-dihydroxy-4,5-dihydrobenzo[a]pyrene. The (-) enantiomer of benzo[a]pyrene 4,5-oxide was 1.5- to 5.5-fold more mutagenic than the (+) enantiomer in strains TA 98, TA 100, TA 1537, and TA 1538 of Salmonella typhimurium and in Chinese hamster V79 cells. In studies with V79 Cells, the (-) enantiomer of benzo[a]pyrene 4,5-oxide was also more cytotoxic than the (+) enantiomer. When mixtures of the enantiomers were studied in V79 cells, synergistic cytotoxic and mutagenic responses were observed. The greatest cytotoxic and mutagenic effects occurred with a 3:1 mixture of the (-) and (+) enantiomers of benzo[a]pyrene 4,5-oxide, respectively.