Chisholm-Burns, M., Spivey, C., Billheimer, D., Schlesselman, L., Hammer, D., Engle, J., Nappi, J., Pasko, M., Ann, R. L., Sorofman, B., Rodrigues, H., & Vaillancourt, A. (2012). Multi-Institutional Study of Women and Underrepresented Minority Faculty Members in Academic Pharmacy. Am J Pharm Educ, 76(1), 7.
Codreanu, S. G., Zhang, B., Sobecki, S. M., Billheimer, D. D., & Liebler, D. C. (2009). Global analysis of protein damage by the lipid electrophile 4-hydroxy-2-nonenal. Molecular and Cellular Proteomics, 8(4), 670-680.
PMID: 19054759;PMCID: PMC2667350;Abstract:
Lipid peroxidation yields a variety of electrophiles, which are thought to contribute to the molecular pathogenesis of diseases involving oxidative stress, yet little is known of the scope of protein damage caused by lipid electrophiles. We identified protein targets of the prototypical lipid electrophile 4-hydroxy-2-nonenal (HNE) in RKO cells treated with 50 or 100 μM HNE. HNE Michael adducts were biotinylated by reaction with biotinamidohexanoic acid hydrazide, captured with streptavidin, and the captured proteins were resolved by one dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis, digested with trypsin, and identified by liquid chromatography-tandem mass spectrometry. Of the 1500+ proteins identified, 417 displayed a statistically significant increase in adduction with increasing HNE exposure concentration. We further identified 18 biotin hydrazide-modified, HNE-adducted peptides by specific capture using anti-biotin antibody and analysis by high resolution liquid chromatography-tandem mass spectrometry. A subset of the identified HNE targets were validated with a streptavidin capture and immunoblotting approach, which enabled detection of adducts at HNE exposures as low as 1 μM. Protein interaction network analysis indicated several subsystems impacted by endogenous electrophiles in oxidative stress, including the 26 S proteasomal and chaperonin containing TCP-1 (CCT) systems involved in protein-folding and degradation, as well as the COP9 signalosome, translation initiation complex, and a large network of ribonucleoproteins. Global analyses of protein lipid electrophile adducts provide a systems-level perspective on the mechanisms of diseases involving oxidative stress. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
Li, H., Canet, M. J., Clarke, J. D., Billheimer, D., Xanthakos, S. A., Lavine, J. E., Erickson, R. P., & Cherrington, N. J. (2017). Pediatric Cytochrome P450 Activity Alterations in Nonalcoholic Steatohepatitis. Drug metabolism and disposition: the biological fate of chemicals, 45(12), 1317-1325.
BIO5 Collaborators
Dean Billheimer, Nathan J Cherrington
Variable drug responses depend on individual variation in the activity of drug-metabolizing enzymes, including cytochrome P450 enzymes (CYP). As the most common chronic liver disease in children and adults, nonalcoholic steatohepatitis (NASH) has been identified as a source of significant interindividual variation in hepatic drug metabolism. Compared with adults, children present age-related differences in pharmacokinetics and pharmacodynamics. The purpose of this study was to determine the impact of fatty liver disease severity on the activity of a variety of CYP enzymes in children and adolescents. Healthy and nonalcoholic fatty liver disease pediatric subjects aged 12-21 years inclusive received an oral cocktail of four probe drugs: caffeine (CYP1A2, 100 mg), omeprazole (CYP2C19, 20 mg), losartan (CYP2C9, 25 mg), and midazolam (CYP3A4, 2 mg). Venous blood and urine were collected before administration and 1, 2, 4, and 6 hours after administration. Concentrations of the parent drugs and CYP-specific metabolites were quantified in plasma and urine using liquid chromatography with tandem mass spectrometry. In plasma, the decreased metabolic area under the curve (AUC) ratio, defined as the metabolite AUC to parent AUC, of omeprazole indicated significant decreases of CYP2C19 (P = 0.002) enzymatic activities in NASH adolescents, while the urine analyses did not show significant differences and were highly variable. A comparison between the present in vivo pediatric studies and a previous ex vivo study in adults indicates distinct differences in the activities of CYP1A2 and CYP2C9. These data demonstrate that pediatric NASH presents an altered pattern of CYP activity and NASH should be considered as a confounder of drug metabolism for certain CYP enzymes. These differences could lead to future investigations that may reveal unexpected variable drug responses that should be considered in pediatric dosage recommendations.
Billheimer, D., Cardoso, T., Freeman, E., Guttorp, P., Ko, H., & Silkey, M. (1997). Natural variability of benthic species composition in the Delaware Bay. Environmental and Ecological Statistics, 4(2), 95-115.
Abstract:
Biological monitoring of aquatic biota is used to assess the impact of changes in the environment. Critical to the development of a sound biological monitoring protocol is the judicious selection of organisms and organism characteristics to be monitored. Accurate interpretations of change necessitate description of the natural variability of the system. We introduce a state-space model for compositional monitoring data, and illustrate how one can incorporate spatial structure and covariates to assess natural variability. The methods are illustrated on benthic survey data from Delaware Bay, and applied to proportional composition at the genus level. The distribution of benthic macroinvertebrates in Delaware Bay depends significantly on salinity. There is residual spatial dependence in the data after accounting for the salinity effect.
Carbone, D. P., Salmon, J. S., Billheimer, D., Chen, H., Sandler, A., Roder, H., Roder, J., Tsypin, M., Herbst, R. S., Tsao, A. S., Tran, H. T., & Dang, T. P. (2010). VeriStrat® classifier for survival and time to progression in non-small cell lung cancer (NSCLC) patients treated with erlotinib and bevacizumab. Lung Cancer, 69(3), 337-340.
PMID: 20036440;PMCID: PMC2891357;Abstract:
We applied an established and commercially available serum proteomic classifier for survival after treatment with erlotinib (VeriStrat®) in a blinded manner to pretreatment sera obtained from recurrent advanced NSCLC patients before treatment with the combination of erlotinib plus bevacizumab. We found that VeriStrat® could classify these patients into two groups with significantly better or worse outcomes and may enable rational selection of patients more likely to benefit from this costly and potentially toxic regimen. © 2009 Elsevier Ireland Ltd.
