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Peter R. Sinclair, Ph.D.
Title(s):
Research Associate Professor of Biochemistry and of Pharmacology & Toxicology
Department(s):
Biochemistry
Pharmacology and Toxicology
Education:
U. Kentucky, PHD 1970U. Sydney, BS 1962U. Sydney, MS 1966
Programs:
Pharmacology and Toxicology Graduate Program
Websites:
http://dms.dartmouth.edu/pharm-tox
Contact Information:
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Office: VA Hospital Phone: 802-295-9363 Fax: 802-296-6308 Email: peter.sinclair@dartmouth.edu Asst. Phone: 802-295-9363 |
Selected Publications: |
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Gorman N., Trask H.W.,. Bement W.J., Szakacs J.G., Elder G.H., Balestra D., Jacobs N.J., Jacobs J.M., Sinclair J.F., Gerhard, G.S., and Sinclair P.R. Genetic factors influence ethanol-induced uroporphyria in Hfe(-/-) mice. Hepatology 40, 942-50 (2004). (view details on MedLine) Uno S., Dalton T.P, Sinclair P.R., Gorman N., Wang B., Smith A.G., Miller M.L., Shertzer H.G., and Nebert D.W. Cyp1a1(-/-) male mice: protection against high-dose TCDD-induced lethality and wasting syndrome, and resistance to intra-hepatocyte lipid accumulation and uroporphyria. Toxicology and Applied Pharmacology;196, 410-21 (2004). (view details on MedLine) Trask HW, Gorman N, Dwyer BE, Jacobs NJ, Jacobs JM, Sinclair JF, Balestra D, Sinclair PR. Effect of insulin and glucagon on accumulation of uroporphyrin and coproporphyrin from 5-aminolevulinate in hepatocyte cultures. Arch Biochem Biophys;439:1-11 (2005). (view details on MedLine) |
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Professional Interests:
Regulation of heme and hemoproteins, particularly in liver cell cultures: mechanisms by which endogenous and exogenous compounds are activated and metabolized by the cytochrome P450 hemoprotein systems.
Dr. Sinclair received his B.S. and his M.S. in 1961 and 1966 respectively, from the University of Sydney. He obtained his Ph.D. in 1970 at the University of Kentucky. After postdoctoral work at Rockefeller University and in London and Zurich he joined the staff of the Veterans Administration Hospital in White River Junction, Vermont in 1977.
Dr. Peter Sinclair's laboratory is interested in the regulation of heme and hemoprotein metabolism, especially in the liver, where most heme is used for synthesis of cytochrome P450. This cytochrome is involved in oxidative metabolism of endogenous steroids and lipids and of exogenous compounds such as drugs and environmental chemicals. Some of these compounds are converted to activated products that can cause cell toxicity or even lead to transformation of the cells. It is now recognized that most chemical carcinogens require such activation.
Most of his studies utilize tissue cultures of chick embryo and adult rat liver cells that retain the inducibility of several cytochrome P450 enzymes and the rate-limiting enzyme of heme biosynthesis, delta-aminolevulinate synthase. The regulation of coordinated heme and hemoprotein synthesis in both chick and rat liver cultures is being studied.
Another major goal is to define the mechanisms whereby a number of polyhalogenated aromatic hydrocarbons such as PCB's and tetrachlorodibenzodioxin (TCDD) cause accumulation of uroporphyrin in animals and humans. A particular cytochrome P450 is involved in the oxidation of uroporphyrinogen to uroporphyrin. Current studies are directed to elucidate the mechanism of this oxidation and the role of ascorbic acid in protection against this oxidation.
Grant Information:
VA Merit Review(Sinclair, P) 10/01/02-9/30/07
Mechanism of Uroporphyria Accumulation by Ethanol
The long-term goal of this grant is to delineate the mechanism by which alcoholic beverages, the major risk factor in human uroporhyria, Porphyria Cutanea Tarda, precipitate uroporhyria, including a role in iron accumulation.
RO1-ES 06263-08 (Sinclair, P.) 7/1/99-6/30/03
NIH/NIEHS
Mechanism of porphyria caused by TCDD.
The overall goals of this research are to characterize the mechanism of development of hepatic uroporhyria caused by polyhalogenated aromatic hydrocarbons and to deterrmine the relationship to the human disease of uroporhyria, Porphyria Cutanea Tarda.
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