Abstract

Previous years of this project have focussed on determining the conditions for maintenance and inducibility of cytochrome P450 in chick hepatocyte in tissue culture. Cytochromes P450 are a class of hemoproteins which are responsible for activation of most carcinogens, the liver being most active in this activation. In this proposal we will extend our studies to characterize the total species of P450's and the Phase II enzyme uridine diphosphoglucuronyl transferase induced by several chemical treatments. The basis relationships between heme metabolism and cytochrome P450 inductions will be investigated in the chick lever culture. We will investigate whether the lower inducibility of P450 in rat liver cell cultures by many of these chemicals may be due to culture-induced changes in heme metabolism or to an inapparopriate extracellular matrix. The protential usefulness of the chick liver culture for carcinogen activation studies will be tested by a) metabolic studies of benz(a)pyrene and acetylaminofluorene, b) carcinogen-mediated mutagenesis in Chinese hamster V79 cells in co-culture with chick liver cells induced for different species of cytochrome P450 and c) DNA lesions produced by chromate and the parallel decrease in inducible enzyme activities.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA025012-08
Application #
3166643
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1978-06-01
Project End
1986-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
8
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
Dartmouth College
Department
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755

  Publications

Sinclair, P R; Gorman, N; Walton, H S et al. (1994) Protoporphyrinogen accumulation in cultured hepatocytes treated with the diphenyl ether herbicide, acifluorfen. Cell Mol Biol (Noisy-le-grand) 40:891-7
Sinclair, P R; Bement, W J; Healey, J F et al. (1994) Effects of hemopexin on heme-mediated repression of 5-aminolevulinate synthase and induction of heme oxygenase in cultured hepatocytes. Hepatology 20:741-6
LeDuc, B W; Sinclair, P R; Walton, H S et al. (1994) Cocaine toxicity in cultured chicken hepatocytes: role of cytochrome P450. Toxicol Appl Pharmacol 125:322-32
Nims, R W; Sinclair, P R; Sinclair, J F et al. (1993) Dose-response relationships for the induction of P450 2B by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzne (TCPOBOP) in rat and cultured rat hepatocytes. Xenobiotica 23:1411-26
Xu, L C; Sinclair, P R; Bresnick, E (1993) Induction of cytochrome P450IA1 and its recombinant construct in H4IIE rat hepatoma cells. Int J Biochem 25:13-21
Potter, D; Chroneos, Z C; Baynes, J W et al. (1993) In vivo fate of hemopexin and heme-hemopexin complexes in the rat. Arch Biochem Biophys 300:98-104
Louis, C A; Sinclair, J F; Wood, S G et al. (1993) Synergistic induction of cytochrome P450 by ethanol and isopentanol in cultures of chick embryo and rat hepatocytes. Toxicol Appl Pharmacol 118:169-76
LeDuc, B W; Sinclair, P R; Shuster, L et al. (1993) Norcocaine and N-hydroxynorcocaine formation in human liver microsomes: role of cytochrome P-450 3A4. Pharmacology 46:294-300
Lindenthal, J; Sinclair, J F; Howell, S et al. (1993) Toxicity of paracetamol in cultured chick hepatocytes treated with methotrexate. Eur J Pharmacol 228:289-98
Sinclair, P R; Gorman, N; Walton, H S et al. (1993) Ascorbic acid inhibition of cytochrome P450-catalyzed uroporphyrin accumulation. Arch Biochem Biophys 304:464-70

Showing the most recent 10 out of 46 publications