F. Peter Guengerich, Ph.D.

Harry Pearson Broquist Professor of Biochemistry 
Director of the Center in Molecular Toxicology 
Ph.D., Vanderbilt University, 1973 (Biochemistry)

Major areas of interest include the metabolism of carcinogens and drugs by cytochrome P450 enzymes, the bioactivation of halogenated hydrocarbons, and polymerase interactions with carcinogen-modified DNA. Several approaches are being used to understand the catalytic mechanisms of the human cytochrome P450 enzymes, including site-directed and random mutagenesis, kinetic analysis, isotope effects, and substrate-activity relationships. Work on halogenated hydrocarbons is done with trichloroethylene, ethylene dibromide, and methylene dihalides and the adducts they form. Glutathione transferase-mediated bioactivation is under investigation, as well as in the case of some bifunctional electrophiles. Studies on the polymerases involve the use of modified oligonucleotides, steady-state and pre-steady-state kinetics, and physical approaches such as x-ray diffraction. A major goal is to understand how carcinogen-DNA adducts cause polymerases to stall and misincorporate bases.

Recent Publications

Murayama N, Minoshima M, Shimizu M, Guengerich FP, Yamazaki H. Involvement of human cytochrome P450 2B6 in the omega- and 4-hydroxylation of the anesthetic agent propofol. Xenobiotica. 2007 37:717-24.

Kolvenbach B, Schlaich N, Raoui Z, Prell J, Zuhlke S, Schaffer A, Guengerich FP, Corvini PF. Degradation pathway of bisphenol A: Does ipso substitution apply to phenols containing a quaternary alpha-carbon structure in the para position? Appl Environ Microbiol. 2007 73:4776-84.

Eoff RL, Irimia A, Angel KC, Egli M, Guengerich FP. Hydrogen bonding of 7,8-dihydro-8-oxodeoxyguanosine with a charged residue in the little finger domain determines miscoding events in Sulfolobus solfataricus DNA polymerase Dpo4. J Biol Chem. 2007 282:19831-43.

Kim HJ, Lee SB, Guengerich FP, Park YI, Dong MS. Effects of N-terminal modification of recombinant human cytochrome P450 1A2 on catalytic activity. Xenobiotica. 2007 37:356-65.

Chun YJ, Shimada T, Sanchez-Ponce R, Martin MV, Lei L, Zhao B, Kelly SL, Waterman MR, Lamb DC, Guengerich FP. Electron transport pathway for a streptomyces cytochrome P450: cytochrome P450 105D5-catalyzed fatty acid hydroxylation in Streptomyces coelicolor A3(2). J Biol Chem. 2007 282:17486-500.

Sanchez-Ponce R, Guengerich FP. Untargeted analysis of mass spectrometry data for elucidation of metabolites and function of enzymes. Anal Chem. 2007 79:3355-62.

Eoff RL, Angel KC, Egli M, Guengerich FP. Molecular basis of selectivity of nucleoside triphosphate incorporation opposite O6-benzylguanine by Sulfolobus solfataricus DNA polymerase Dpo4: steady-state and pre-steady-state kinetics and x-ray crystallography of correct and incorrect pairing. J Biol Chem. 2007 282:13573-84.

Guengerich FP, MacDonald JS. Applying mechanisms of chemical toxicity to predict drug safety. Chem Res Toxicol. 2007 20:344-69.

Shimada T, Murayama N, Okada K, Funae Y, Yamazaki H, Guengerich FP. Different mechanisms for inhibition of human cytochromes P450 1A1, 1A2, and 1B1 by polycyclic aromatic inhibitors. Chem Res Toxicol. 2007 20:489-96.

Isin EM, Guengerich FP. Complex reactions catalyzed by cytochrome P450 enzymes. Biochim Biophys Acta. 2007 1770:314-29.

Liu L, Watanabe K, Fang Q, Williams KM, Guengerich FP, Pegg AE. Effect of alterations of key active site residues in O6-alkylguanine-DNA Alkyltransferase on its ability to modulate the genotoxicity of 1,2-dibromoethane. Chem Res Toxicol. 2007 20:155-63.

Warzecha H, Frank A, Peer M, Gillam EM, Guengerich FP, Unger M. Formation of the indigo precursor indican in genetically engineered tobacco plants and cell cultures. Plant Biotechnol J. 2007 5:185-91.

Isin EM, Guengerich FP. Multiple sequential steps involved in the binding of inhibitors to cytochrome P450 3A4. J Biol Chem. 2007 282:6863-74.

Yamazaki H, Okayama A, Imai N, Guengerich FP, Shimizu M. Inter-individual variation of cytochrome P4502J2 expression and catalytic activities in liver microsomes from Japanese and Caucasian populations. Xenobiotica. 2006 36:1201-9.

Stover JS, Chowdhury G, Zang H, Guengerich FP, Rizzo CJ. Translesion synthesis past the C8- and N2-deoxyguanosine adducts of the dietary mutagen 2-amino-3-methylimidazo[4,5-f]quinoline in the NarI recognition sequence by prokaryotic DNA polymerases. Chem Res Toxicol. 2006 19:1506-17.

Eoff RL, Irimia A, Egli M, Guengerich FP. Sulfolobus solfataricus DNA polymerase Dpo4 is partially inhibited by "wobble" pairing between O6-methylguanine and cytosine, but accurate bypass is preferred. J Biol Chem. 2007 282:1456-67.

Chun YJ, Shimada T, Waterman MR, Guengerich FP. Understanding electron transport systems of Streptomyces cytochrome P450. Biochem Soc Trans. 2006 34:1183-5.

Oda Y, Totsuka Y, Wakabayashi K, Guengerich FP, Shimada T. Activation of aminophenylnorharman, aminomethylphenylnorharman and aminophenylharman to genotoxic metabolites by human N-acetyltransferases and cytochrome P450 enzymes expressed in Salmonella typhimurium umu tester strains. Mutagenesis. 2006 21:411-6.

Choi JY, Chowdhury G, Zang H, Angel KC, Vu CC, Peterson LA, Guengerich FP. Translesion synthesis across O6-alkylguanine DNA adducts by recombinant human DNA polymerases. J Biol Chem. 2006 281:38244-56.

Guengerich FP. A malleable catalyst dominates the metabolism of drugs. Proc Natl Acad Sci U S A. 2006 103:13565-6.

Zipes DP, Zvaifler NJ, Glassock RJ, Gilman S, Munoz A, Gogolak V, Gordis L, Dedon PC, Guengerich FP, Wasserman SI, Witztum JL, Wogan GN. Rosuvastatin: an independent analysis of risks and benefits. Med Gen Med. 2006 8:73. Review.

Watanabe K, Guengerich FP. Limited reactivity of formyl chloride with glutathione and relevance to metabolism and toxicity of dichloromethane. Chem Res Toxicol. 2006 19:1091-6.

Lamb DC, Guengerich FP, Kelly SL, Waterman MR. Exploiting Streptomyces coelicolor A3(2) P450s as a model for application in drug discovery. Expert Opin Drug Metab Toxicol. 2006 2:27-40.

Choi JY, Stover JS, Angel KC, Chowdhury G, Rizzo CJ, Guengerich FP. Biochemical basis of genotoxicity of heterocyclic arylamine food mutagens: Human DNA polymerase eta selectively produces a two-base deletion in copying the N2-guanyl adduct of 2-amino-3-methylimidazo[4,5-f]quinoline but not the C8 adduct at the NarI G3 site. J Biol Chem. 2006 281:25297-306.

Choi JY, Zang H, Angel KC, Kozekov ID, Goodenough AK, Rizzo CJ, Guengerich FP. Translesion synthesis across 1,N2-ethenoguanine by human DNA polymerases. Chem Res Toxicol. 2006 19:879-86.

Zang H, Chowdhury G, Angel KC, Harris TM, Guengerich FP. Translesion synthesis across polycyclic aromatic hydrocarbon diol epoxide adducts of deoxyadenosine by Sulfolobus solfataricus DNA polymerase Dpo4. Chem Res Toxicol. 2006 19:859-67.

Choi JY, Angel KC, Guengerich FP. Translesion synthesis across bulky N2-alkyl guanine DNA adducts by human DNA polymerase kappa. J Biol Chem. 2006 281:21062-72.

Guengerich FP, Martin MV. Purification of cytochromes P450: products of bacterial recombinant expression systems. Methods Mol Biol. 2006 320:31-7.

Bren U, Zupan M, Guengerich FP, Mavri J. Chemical reactivity as a tool to study carcinogenicity: reaction between chloroethylene oxide and guanine. J Org Chem. 2006 71:4078-84.

Irimia A, Zang H, Loukachevitch LV, Eoff RL, Guengerich FP, Egli M. Calcium is a cofactor of polymerization but inhibits pyrophosphorolysis by the Sulfolobus solfataricus DNA polymerase Dpo4. Biochemistry. 2006 45:5949-56.

Kim KH, Isin EM, Yun CH, Kim DH, Guengerich FP. Kinetic deuterium isotope effects for 7-alkoxycoumarin O-dealkylation reactions catalyzed by human cytochromes P450 and in liver microsomes. Rate-limiting C-H bond breaking in cytochrome P450 1A2 substrate oxidation. FEBS J. 2006 273:2223-31.

Jiang Z, Dragin N, Jorge-Nebert LF, Martin MV, Guengerich FP, Aklillu E, Ingelman-Sundberg M, Hammons GJ, Lyn-Cook BD, Kadlubar FF, Saldana SN, Sorter M, Vinks AA, Nassr N, von Richter O, Jin L, Nebert DW. Search for an association between the human CYP1A2 genotype and CYP1A2 metabolic phenotype. Pharmacogenet Genomics. 2006 16:359-67.

Guengerich FP. Cytochrome P450s and other enzymes in drug metabolism and toxicity. AAPS J. 2006 8:E101-11. Review.

Wu ZL, Sohl CD, Shimada T, Guengerich FP. Recombinant enzymes overexpressed in bacteria show broad catalytic specificity of human cytochrome P450 2W1 and limited activity of human cytochrome P450 2S1. Mol Pharmacol. 2006 69:2007-14.

Choi JY, Guengerich FP. Kinetic evidence for inefficient and error-prone bypass across bulky N2-guanine DNA adducts by human DNA polymerase iota. J Biol Chem. 2006 281:12315-24.

Shimada T, Guengerich FP. Inhibition of human cytochrome P450 1A1-, 1A2-, and 1B1-mediated activation of procarcinogens to genotoxic metabolites by polycyclic aromatic hydrocarbons. Chem Res Toxicol. 2006 19:288-94.

Isin EM, Guengerich FP. Kinetics and thermodynamics of ligand binding by cytochrome P450 3A4. J Biol Chem. 2006 281:9127-36.

Guengerich FP. Interactions of carcinogen-bound DNA with individual DNA polymerases. Chem Rev. 2006 106:420-52. Review.

Guengerich FP. Activation of alkyl halides by glutathione transferases. Methods Enzymol. 2005 401:342-53.

Wu ZL, Bartleson CJ, Ham AJ, Guengerich FP. Heterologous expression, purification, and properties of human cytochrome P450 27C1. Arch Biochem Biophys. 2006 445:138-46.

Zang H, Irimia A, Choi JY, Angel KC, Loukachevitch LV, Egli M, Guengerich FP. Efficient and high fidelity incorporation of dCTP opposite 7,8-dihydro-8-oxodeoxyguanosine by Sulfolobus solfataricus DNA polymerase Dpo4. J Biol Chem. 2006 281:2358-72.