Most occupational exposures to toxic chemicals occur in the context of complex mixtures, often in combination with varied diet, prescription drug use and disease. In principle, information-rich metabolic analyses provide an approach to study toxicologic consequences of such complex chemical interactions by revealing metabolic perturbations before irreversible injury occurs. This pilot study tests the feasibility of using GSH redox state and high-resolution proton NMR spectroscopy (1H-NMR) to detect metabolic changes due to chemical interactions. The proposed model involves interaction of chemical exposure (2 doses of acetaminophen, APAP, 15 mg/kg) and 2 days of sulfur amino acid- (SAA-) free diet. 30% of APAP metabolism occurs through pathways dependent upon SAA metabolites and up to 50% of the RDA for SAA is needed to metabolize 2 doses of APAP. Both treatments are without toxicity in humans and both affect GSH homeostasis, which will be assessed in vivo by plasma measurements. Inter-individual variation will be minimized with each individual being his/her own control. Environmental and dietary influences will be controlled in a clinical research unit.
Aim 1 is to determine whether SAA-free diet and APAP independently perturb GSH redox homeostasis.
Aim 2 is to determine whether APAP intake interacts with SAA-free diet in affecting GSH redox state.
Aim 3 is to use 1H-NMR spectroscopy to determine whether exposure to APAP and SAA-free diet interact in their effects on metabolic profile. The results will provide key data on the suitability and sensitivity of redox measurements and 1H-NMR spectroscopy for study of chemical interactions. This could provide a foundation for the use of perturbation of metabolic profile as a means to identify risks and consequences of complex chemical mixtures, which would be especially relevant to occupational exposures in combination with therapeutic drugs and other health risk factors. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Small Research Grants (R03)
Project #
1R03ES012929-01
Application #
6762136
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Thompson, Claudia L
Project Start
2004-09-01
Project End
2006-05-31
Budget Start
2004-09-01
Budget End
2005-05-31
Support Year
1
Fiscal Year
2004
Total Cost
$76,500
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Park, Youngja; Lee, Kichun; Ziegler, Thomas R et al. (2013) Multifractal analysis for nutritional assessment. PLoS One 8:e69000
Park, Youngja; Zhao, Tiejun; Miller, Nana Gletsu et al. (2012) Sulfur amino acid-free diet results in increased glutamate in human midbrain: a pilot magnetic resonance spectroscopic study. Nutrition 28:235-41
Park, Youngja; Le, Ngoc-Anh; Yu, Tianwei et al. (2011) A sulfur amino acid-free meal increases plasma lipids in humans. J Nutr 141:1424-31
Jones, Dean P; Park, Youngja; Gletsu-Miller, Nana et al. (2011) Dietary sulfur amino acid effects on fasting plasma cysteine/cystine redox potential in humans. Nutrition 27:199-205
Park, Youngja; Ziegler, Thomas R; Gletsu-Miller, Nana et al. (2010) Postprandial cysteine/cystine redox potential in human plasma varies with meal content of sulfur amino acids. J Nutr 140:760-5
Mannery, Yanci O; Ziegler, Thomas R; Park, Youngja et al. (2010) Acetaminophen elimination half-life in humans is unaffected by short-term consumption of sulfur amino acid-free diet. J Pharmacol Exp Ther 333:948-53
Mannery, Yanci O; Ziegler, Thomas R; Park, Youngja et al. (2010) Oxidation of plasma cysteine/cystine and GSH/GSSG redox potentials by acetaminophen and sulfur amino acid insufficiency in humans. J Pharmacol Exp Ther 333:939-47
Park, Youngja; Kim, Seoung Bum; Wang, Bing et al. (2009) Individual variation in macronutrient regulation measured by proton magnetic resonance spectroscopy of human plasma. Am J Physiol Regul Integr Comp Physiol 297:R202-9
Kemp, Melissa; Go, Young-Mi; Jones, Dean P (2008) Nonequilibrium thermodynamics of thiol/disulfide redox systems: a perspective on redox systems biology. Free Radic Biol Med 44:921-37