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Biomedical subjects

J E Rice

Publications and source records attributed to J E Rice.

42 records · Page 3Linked to original sources
PubMed1985

Identification of mutagenic metabolites of indeno[1,2,3-cd]pyrene formed in vitro with rat liver enzymes.

Indeno[1,2,3-cd]pyrene (IP) is a major environmental pollutant which is carcinogenic on mouse skin and in rat lung. Unlike benzo(a)pyrene, IP is a nonalternant polycyclic aromatic hydrocarbon which is devoid of a bay region. IP was mutagenic in Salmonella typhimurium TA100 in the presence of a 9000 X g supernatant from the livers of Aroclor-pretreated rats. Using a similar activation system, the major metabolites of IP were isolated and identified by comparison with synthetic reference standards. trans-1,2-Dihydro-1,2-dihydroxy-IP, 8-, 9-, and 10-hydroxy-IP, 8- and 9-hydroxy-trans-1,2-dihydro-1,2-dihydroxy-IP, and IP-1,2-quinone are among the metabolites formed in vitro. The 1,2-epoxide of indeno[1,2,3-cd]pyrene is a potent direct-acting mutagen. 8- and 9-hydroxy-IP were mutagenic with metabolic activation. 1-,2-, and 6-hydroxy-IP and the trans-1,2-dihydrodiol had no significant mutagenic activity in S. typhimurium TA100 with metabolic activation. These data suggest that the K-region oxides of IP and of 8- and 9-hydroxy-IP are ultimately responsible for its mutagenic activity.

Animals↗
PubMed1984

Fluoranthene and pyrene enhance benzo[a]pyrene--DNA adduct formation in vivo in mouse skin.

Fluoranthene and pyrene are potent cocarcinogens when applied together with benzo[a]pyrene (BaP) on mouse skin. In this study the effect of fluoranthene, pyrene and phenanthrene on the formation of BaP--DNA adducts in mouse skin was investigated. Co-application of either fluoranthene or pyrene with [3H]BaP resulted in an average increase in the level of [3H]BaP--DNA adducts of 56% to 66%, respectively, as compared to [3H]BaP alone. Only minor differences were observed in the ratio of (+/-)anti- to (+/-)synbenzo[a]pyrene diol epoxide--DNA adducts between experimental groups. An average 17% decrease in the formation of [3H]BaP--DNA adducts was observed upon co-application of [3H]BaP on mouse skin with phenanthrene. These data suggest a correlation between the observed increase in tumorigenicity of BaP in the presence of either fluoranthene or pyrene and an increase in the formation of (+/-)anti-benzo[a]pyrene diol epoxide--DNA adducts.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1981

The influence of immaturity on hypoxic-ischemic brain damage in the rat.

Brain damage in the Levine preparation (unilateral common carotid artery ligation with hypoxia) consists of ischemic neuronal alterations in the ipsilateral forebrain. As the model has been restricted to adult animals, unilateral common carotid artery ligation was carried out in 7-day-postnatal rats. Four to 8 hours later the 25 pups were exposed to 8% oxygen at 37 degrees C for 3.5 hours. Controls consisted of littermates subjected to carotid ligation without subsequent hypoxia, hypoxia without prior ligation, and neither ligation nor hypoxia. After hypoxia the animals were returned to their dams and appeared normal for up to 50 hours. All pups were then killed by perfusion-fixation. Moderate to severe ischemic neuronal changes were seen in the ipsilateral cerebral cortex, striatum, and hippocampus in at least 90% of the animals and included infarction in 56% of the brains. Cortical damage was occasionally laminar but more often occurred in columns at right angles to the pial surface. Unlike adult animals, there was necrosis of white matter, greater ipsilaterally, originating in and spreading from myelinogenic foci. The evolution of ischemic cell change and the associated gliomesodermal reaction was more rapid than in the adult. In 22 additional pups subjected to carotid artery ligation and hypoxia, brains were analyzed for water content. Significant increases (0.6 to 3.3%) in water content of the ipsilateral hemispheres occurred in 11 of 22 brains (50%). Unilateral ischemia combined with hypoxia in developing rats therefore results in neuronal destruction in the same brain regions as in adult animals, but also causes necrosis of white matter. The incidence of increased water content was similar to that of overt infarction. Thus, as previously shown in the adult, brain edema is a consequence rather than a cause of major ischemic damage in the immature animal.

Age Factors↗
PubMedDate not supplied

Detection of the major DNA adducts of benzo[b]fluoranthene in mouse skin: role of phenolic dihydrodiols.

The primary mechanism of activation of benzo[b]fluoranthene (B[b]F) to a genotoxic agent does not involve the bay region dihydrodiol epoxide trans-9,10-dihydroxy-anti- 11,12-epoxy-9,10,11,12-tetrahydrobenzo[b]fluoranthene (B[b]F-9,10-DE). Previous results have suggested that the major DNA adduct(s) formed in vivo with B[b]F are more polar than those formed from B[b]F-9,10-DE. Employing newly-developed synthetic methods for the formation of B[b]F derivatives, trans-9,10-dihydro-5,9,10-trihydroxybenzo[b]fluoranthene (5-OH-B[b]F-9,10-diol) and trans-9,10-dihydro-6,9,10-trihydroxybenzo[b]fluoranthene (6-OH-B[b]F-9,10-diol) were synthesized and evaluated for tumor-initiating activity at initiation doses of 0.04, 0.12, and 0.4 mumol per mouse. In contrast to previous bioassay results, both of these phenolic dihydrodiols exhibited tumor-initiating activity. 5-OH-B[b]F-9,10-diol was the more potent tumor initiator, inducing a 90% incidence of tumor-bearing mice with an average of 7.50 tumors per mouse at a total initiator dose of 0.4 mumol. 6-OH-B[b]F-9,10-diol was significantly less active as a tumor initiator in this bioassay, inducing a 50% incidence of tumor-bearing mice with an average of 0.60 tumor per mouse at a total dose of 0.4 mumol. 32P-Postlabeling analysis was employed to evaluate the DNA adducts formed in vivo in mouse skin from both 5- and 6-OH-B[b]F-9,10-diol. HPLC analysis of B[b]F-DNA adducts formed in mouse skin demonstrated the presence of a single major adduct together with four additional minor adducts. The DNA adducts formed with 5-OH-B[b]F-9,10-diol had identical HPLC retention to the major and one of the minor adducts observed for B[b]F. These two DNA adducts account for 58% of the modified nucleotides detected in mouse skin following the topical application of B[b]F. Methods for the preparation of trans-9,10-dihydroxy-anti-11,12-epoxy-5-hydroxy-9,10,11,12- tetrahydrobenzo[b]fluoranthene (5-OH-B[b]F-9,10-DE) were developed. The DNA adducts formed with 5-OH-B[b]F-9,10-DE were similar to the adducts formed with 5-OH-B[b]F-9,10-diol. The results of the DNA binding studies along with the tumor-initiating data indicate that 5-OH-B[b]F-9,10-diol is the major proximate tumorigenic metabolite of B[b]F on mouse skin. Studies performed with deoxyguanosine 3'-phosphate suggest that the principal adducts formed with anti-5-OH-B[b]F-9,10-DE are the result of the interaction with deoxyguanosine.

Animals↗