Abstract

This proposal represents a continuation of our studies on aflatoxins and cytochromes P-450. The focus of the studies is on the initial steps of aflatoxin B1 (AFB1) carcinogenesis including: (a) activation and deactivation of AFB1 by various cytochromes P-450; (b) elucidation of the genetic regulation of these cytochromes P-450; (c) investigation of the genetic and molecular mechanisms involved in the repression of the cytochromes during multistage hepatocarcinogenesis; and (d) investigation of the molecular and genetic bases of the relationship between cytochromes P-450 repression and induction of hepatocarcinogenesis by AFB1. Various cytochromes P-450 involved in the preferential metabolism of AFB1 via activation and deactivation pathways will be isolated to develop molecular probes (cDNA, genomic DNA). These molecular probes will be characterized and used to elucidate: (a) molecular basis of regioselectivity of various cytochromes P-450 in the metabolism of AFB1 via various pathways; and (b) genetic and molecular alterations required to induce cytochromes P-450 repression during multistage hepatocarcinogenesis. Much of the work will be performed in vivo in rats and in vitro with labeled aflatoxins, bacterial mutagenesis systems, RNA, DNA, and cytochromes P-450 isolated from rats. Particular methods to be used include: radiochemical methods, high pressure liquid chromatography, biochemical and enzymologic methods, ultra-centrifugation, hybridoma and recombinant DNA techniques.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA025362-11
Application #
3166835
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1979-07-01
Project End
1992-11-30
Budget Start
1990-12-01
Budget End
1992-11-30
Support Year
11
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263

  Publications

Habib, S L; Srikanth, N S; Scappaticci, F A et al. (1994) Altered expression of cytochrome P450 mRNA during chemical-induced hepatocarcinogenesis and following partial hepatectomy. Toxicol Appl Pharmacol 124:139-48
Maccubbin, A; Evans, M; Paul, C R et al. (1991) Enzymatic excision of radiation-induced lesions from DNA model compounds. Radiat Res 126:21-6
Paul, C R; Budzinski, E E; Maccubbin, A et al. (1990) Characterization of radiation-induced damage in d(TpApCpG). Int J Radiat Biol 58:759-68
Faletto, M B; Maccubbin, A E; Ersing, N et al. (1990) Altered benzo[a]pyrene metabolism in C3H/10T1/2 cells transformed by aflatoxin B1 or 3-methylcholanthrene. Toxicol Appl Pharmacol 104:351-66
Faletto, M B; Gurtoo, H L (1989) The effect of inducers of mixed-function oxidases on hepatic microsome-mediated aflatoxin B1 transformation in C3H/10T1/2 cells. Toxicol Appl Pharmacol 98:252-62
Faletto, M B; Maccubbin, A E; Koser, P L et al. (1989) Induction of aryl hydrocarbon hydroxylase and DNA adduct formation in parental and carcinogen transformed C3H/10T1/2 clone 8 cells by benzo[a]pyrene. Cancer Biochem Biophys 10:197-205
Faletto, M B; Koser, P L; Battula, N et al. (1988) Cytochrome P3-450 cDNA encodes aflatoxin B1-4-hydroxylase. J Biol Chem 263:12187-9
Koser, P L; Faletto, M B; Maccubbin, A E et al. (1988) The genetics of aflatoxin B1 metabolism. Association of the induction of aflatoxin B1-4-hydroxylase with the transcriptional activation of cytochrome P3-450 gene. J Biol Chem 263:12584-95
Koser, P L; Faletto, M B; Bansal, S K et al. (1987) Aflatoxin B1-4-hydroxylase is associated with cytochrome P3-450 in C57BL/6 mouse liver. Biochem Biophys Res Commun 142:872-8
Raina, V; Gurtoo, H L (1985) Effects of vitamins A, C, and E on aflatoxin B1-induced mutagenesis in Salmonella typhimurium TA-98 and TA-100. Teratog Carcinog Mutagen 5:29-40

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