Antibodies as a Probe in Cytochrome P450 Research

Magang Shou; Anthony Y. H. Lu

doi:10.1124/dmd.108.025718

Abstract

Cytochrome P450 (P450) is the superfamily of enzymes responsible for biotransformation of endobiotics and xenobiotics. However, their large isoform multiplicity, inducibility, diverse structure, widespread distribution, polymorphic expression, and broad overlapping substrate specificity make it difficult to measure the precise role of each individual P450 to the metabolism of drugs (or carcinogens) and hamper the understanding of the relationship between the genetic/environmental factors that regulate P450 phenotype and the responses of the individual P450s to drugs. The antibodies against P450s have been useful tools for the quantitative determination of expression level and contribution of the epitope-specific P450 to the metabolism of a drug or carcinogen substrate in tissues containing multiple P450 isoforms and for implications in pharmacogenetics and human risk assessment. In particular, the inhibitory antibodies are uniquely suited for reaction phenotyping that helps to predict human pharmacokinetics for clinical drug-drug interaction potential in drug discovery and development.

Footnotes

Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.108.025718.
ABBREVIATIONS: P450, cytochrome P450; f_m, fraction of drug metabolized; DDI, drug-drug interaction; ADME, absorption, distribution, metabolism, and elimination; 3MC, 3-methylcholantheren; PB, phenobarbital; PCN, pregnenolone-16α-carbonitrile; MAb, monoclonal antibody; ELISA, enzyme-linked immunosorbent assay; RIA, radioimmunoassay; HLM, human liver microsomes; GST, glutathione S-transferase; PMNs, polymorphic neutrophils; AFB₁, aflatoxin B₁; NHBE, normal human bronchial epithelial.
Magang Shou received his Ph.D. in Pharmacology under the direction of Dr. Shen K. Yang at the Uniformed Services University of Health Sciences School of Medicine, Bethesda, MD (1986–1991). His Ph.D. dissertation was focused on the stereoselective metabolism and bioactivation of 3-methylcholanthrene and its derivatives in rat liver microsomes. Before joining Amgen in 2006, he was a Postdoctoral Fellow in the Department of Pharmacology (Dr. Trevor M. Penning), University of Pennsylvania School of Medicine, Philadelphia, PA (1991), a Senior Staff Fellow in the Laboratory of Molecular Carcinogenesis (Drs. Kenneth R. Korzekwa and Harry V. Gelboin), National Cancer Institute, National Institutes of Health, Bethesda, MD (1991–1996), and Senior Investigator in the Department of Drug Metabolism, Merck Research Laboratories, West Point, PA (1996–2006). Dr. Shou is currently a Scientific Director of the Department of Pharmacokinetics and Drug Metabolism at Amgen. His major research interests include 1) drug metabolism and pharmacokinetics in drug discovery and preclinical development; 2) mechanistic and kinetic studies on the cytochrome P450 reactions and drug transport; 3) metabolism-based drug-drug interactions and in vitro-in vivo correlations; and 4) pharmacokinetic/pharmacodynamic modeling and simulation. Dr. Shou has published over 100 peer-reviewed research articles and 5 book chapters and has been on the Editorial Board of several scientific journals, such as Drug Metabolism and Disposition.
Anthony Lu received his Ph.D. degree in Biochemistry from the University of North Carolina and did his postdoctoral work with Professor Minor J. Coon at the University of Michigan. The focus of his postdoctoral research was on the solubilization, resolution, and reconstitution of the cytochrome P450 system. He spent the next 30 years working in the area of drug metabolism, first at Hoffmann-La Roche then at Merck Research Laboratories. In addition to pursuing his research interests on the structure, function, and regulation of cytochrome P450, he was heavily involved in preclinical and clinical ADME studies, particularly the application of basic cytochrome P450 knowledge in support of drug discovery and development. After his retirement from Merck in 1997, he joined the Department of Chemical Biology, College of Pharmacy, Rutgers University as an adjunct Professor. He is currently involved in teaching, consulting, and research related to individual variability in drug response and drug safety, and various ADME issues in drug discovery and development. He is an author or coauthor of 250 research articles, and received the B. B. Brodie Award in drug metabolism in 1996. The 1998 December issue of Drug Metabolism and Disposition was dedicated to honor his contributions to drug metabolism research.
- Received November 17, 2008.
- Accepted January 29, 2009.