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Activation of Dihaloalkanes by Thiol-dependent Mechanisms
Guengerich, F. Peter Korean Society for Biochemistry and Molecular Biol 2003 Journal of biochemistry and molecular biology Vol.36 No.1
Dihaloalkanes constitute an important group of chemicals because of their widespread use in industry and agriculture and their potential for causing toxicity and cancer. Chronic toxic effects are considered to depend upon bioactivation, either by oxidation or thiol conjugation. Considerable evidence links genotoxicity and cancer with glutathione conjugations reactions, and some aspects of the mechanisms have been clarified with 1,2-dihaloalkanes and dihalomethanes. Recently the DNA repair protein $O^6$-alkylguanine transferase has been shown to produce cytotoxicity and genotoxicity by mans of a thiol-dependent process with similarities to the glutathione reactions.
A history of the roles of cytochrome P450 enzymes in the toxicity of drugs
Guengerich F. Peter 한국독성학회 2021 Toxicological Research Vol.37 No.1
The history of drug metabolism began in the 19th Century and developed slowly. In the mid-20th Century the relationship between drug metabolism and toxicity became appreciated, and the roles of cytochrome P450 (P450) enzymes began to be defined in the 1960s. Today we understand much about the metabolism of drugs and many aspects of safety assessment in the context of a relatively small number of human P450s. P450s affect drug toxicity mainly by either reducing exposure to the parent molecule or, in some cases, by converting the drug into a toxic entity. Some of the factors involved are enzyme induction, enzyme inhibition (both reversible and irreversible), and pharmacogenetics. Issues related to drug toxicity include drug–drug interactions, drug-food interactions, and the roles of chemical moieties of drug candidates in drug discovery and development. The maturation of the field of P450 and drug toxicity has been facilitated by advances in analytical chemistry, computational capability, biochemistry and enzymology, and molecular and cell biology. Problems still arise with P450s and drug toxicity in drug discovery and development, and in the pharmaceutical industry the interaction of scientists in medicinal chemistry, drug metabolism, and safety assessment is critical for success.
Inhibition of Cytochrome P450 Enzymes by Drugs―Molecular Basis and Practical Applications
( F. Peter Guengerich ) 한국응용약물학회 2022 Biomolecules & Therapeutics(구 응용약물학회지) Vol.30 No.1
Drug-drug interactions are a major cause of hospitalization and deaths related to drug use. A large fraction of these is due to inhibition of enzymes involved in drug metabolism and transport, particularly cytochrome P450 (P450) enzymes. Understanding basic mechanisms of enzyme inhibition is important, particularly in terms of reversibility and the use of the appropriate parameters. In addition to drug-drug interactions, issues have involved interactions of drugs with foods and natural products related to P450 enzymes. Predicting drug-drug interactions is a major effort in drug development in the pharmaceutical industry and regulatory agencies. With appropriate in vitro experiments, it is possible to stratify clinical drug-drug interaction studies. A better understanding of drug interactions and training of physicians and pharmacists has developed. Finally, some P450s have been the targets of drugs in some cancers and other disease states.
Review : Activation of Dihaloalkanes by Thiol-dependent Mechanisms
( F. Peter Guengerich ) 생화학분자생물학회 2003 BMB Reports Vol.36 No.1
Dihaloalkanes constitute an important group of chemicals because of their widespread use in industry and agriculture and their potential for causing toxicity and cancer. chronic toxic effects are considered to depend upon bioactivation, either by oxidation or thiol conjugation. Considerable evidence links genotoxicity and cancer with glutathione conjugations reactions, and some aspects of the mechanism have been clarified with 1,2-dihaloalkanes and dihalomethanes. Recently the DNA repair protein O^6-allylguanine transferase has been shown to produce cytotoxicity and genotoxicity by means of a thiol-dependent process with similarities to the glutathione reactions.
Lim, Seonhee,Song, Insil,Guengerich, F. Peter,Choi, Jeong-Yun American Chemical Society 2012 Chemical research in toxicology Vol.25 No.8
<P>Archaeal and eukaryotic B-family DNA polymerases (pols) mainly replicate chromosomal DNA but stall at lesions, which are often bypassed with Y-family pols. In this study, a B-family pol Vent (exo<SUP>–</SUP>) from the euryarchaeon <I>Thermococcus litoralis</I> was studied with three types of DNA lesions<I>N</I><SUP>2</SUP>-alkylG, <I>O</I><SUP>6</SUP>-alkylG, and an abasic (AP) sitein comparison with a model Y-family pol Dpo4 from <I>Sulfolobus solfataricus</I>, to better understand the effects of various DNA modifications on binding, bypass efficiency, and fidelity of pols. Vent (exo<SUP>–</SUP>) readily bypassed <I>N</I><SUP>2</SUP>-methyl(Me)G and <I>O</I><SUP>6</SUP>-MeG, but was strongly blocked at <I>O</I><SUP>6</SUP>-benzyl(Bz)G and <I>N</I><SUP>2</SUP>-BzG, whereas Dpo4 efficiently bypassed <I>N</I><SUP>2</SUP>-MeG and <I>N</I><SUP>2</SUP>-BzG and partially bypassed <I>O</I><SUP>6</SUP>-MeG and <I>O</I><SUP>6</SUP>-BzG. Vent (exo<SUP>–</SUP>) bypassed an AP site to an extent greater than Dpo4, corresponding with steady-state kinetic data. Vent (exo<SUP>–</SUP>) showed ∼110-, 180-, and 300-fold decreases in catalytic efficiency (<I>k</I><SUB>cat</SUB>/<I>K</I><SUB>m</SUB>) for nucleotide insertion opposite an AP site, <I>N</I><SUP>2</SUP>-MeG, and <I>O</I><SUP>6</SUP>-MeG but ∼1800- and 5000-fold decreases opposite <I>O</I><SUP>6</SUP>-BzG and <I>N</I><SUP>2</SUP>-BzG, respectively, as compared to G, whereas Dpo4 showed little or only ∼13-fold decreases opposite <I>N</I><SUP>2</SUP>-MeG and <I>N</I><SUP>2</SUP>-BzG but ∼260–370-fold decreases opposite <I>O</I><SUP>6</SUP>-MeG, <I>O</I><SUP>6</SUP>-BzG, and the AP site. Vent (exo<SUP>–</SUP>) preferentially misinserted G opposite <I>N</I><SUP>2</SUP>-MeG, T opposite <I>O</I><SUP>6</SUP>-MeG, and A opposite an AP site and <I>N</I><SUP>2</SUP>-BzG, while Dpo4 favored correct C insertion opposite those lesions. Vent (exo<SUP>–</SUP>) and Dpo4 both bound modified DNAs with affinities similar to unmodified DNA. Our results indicate that Vent (exo<SUP>–</SUP>) is as or more efficient as Dpo4 in synthesis opposite <I>O</I><SUP>6</SUP>-MeG and AP lesions, whereas Dpo4 is much or more efficient opposite (only) <I>N</I><SUP>2</SUP>-alkylGs than Vent (exo<SUP>–</SUP>), irrespective of DNA-binding affinity. Our data also suggest that Vent (exo<SUP>–</SUP>) accepts nonbulky DNA lesions (e.g., <I>N</I><SUP>2</SUP>- or <I>O</I><SUP>6</SUP>-MeG and an AP site) as manageable substrates despite causing error-prone synthesis, whereas Dpo4 strongly favors minor-groove <I>N</I><SUP>2</SUP>-alkylG lesions over major-groove or noninstructive lesions.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/crtoec/2012/crtoec.2012.25.issue-8/tx300168p/production/images/medium/tx-2012-00168p_0003.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/tx300168p'>ACS Electronic Supporting Info</A></P>
Young-Jin Chun,F. Peter Guengerich 한국독성학회 2002 Toxicological Research Vol.18 No.3
Cytochrome P450 3As such as 3A4 and 3A5 metaboize a wide range of pharmaceutical compounds. The vectors for the expression of fusion proteins containing an N-termical human P450 3A4 or P450 3A5 sequences and a C-termical rat NADPH-cytochrome P450 reductase moiety were constructed. These plasmide were used to express the fusion proteins in Escherichia coli DH5α cells. High levels of expression were achieved (100~200 nmol/liter) and the expressed fusion proteins in E. coli membranes were catalytically active for nifedipine oxidation, a typical enzymatic activity of P450 3A4. The NADPH-P450 reductase activities of these fusion proteins were also determined by measuring reduction of cytochrome c. To find a specific inhibitor of P450 3A4 from naturally accurring chemicals, a series of isothiocyanate compounds were evaluated for the inhibitory activity of P450 using the fusion proteins in E. coli membranes. Of the five isothiocyanates (phenethyl isothiocynate, phenyl isothiocyanate, benzyl isothiocyanate, benzoyl isothiocyanate and cyclohexyl isothiocyanate) tested, benzoyl isothiocyanate showed a strong inhibition of P450 3A4 with an IC_(50) value of 2.8μM. Our results indicate that the self-sufficient fusion proteins will be very useful tool to study the drug metabolism and benzyl isothiocyanate may be valuable for characterizing the enzymatic properties of P450 3A4.
Chun, Young-Jin,Guengerich, F-Peter Korean Society of ToxicologyKorea Environmental Mu 2002 Toxicological Research Vol.18 No.3
Cytochrome P450 3As such as 3A4 and 3A5 metabolize a wide range of pharmaceutical compounds. The vectors for the expression of fusion protein containing an N-terminal human P450 3A4 or P450 3A5 sequences and a C-terminal rat NADPH-cytochrome P450 reductase moiety were constructed. These plasmids were used to express the fusion protein in Escherichia coli DH5$\alpha$ cells. High levels of expression were achieved (100~200 nmol/liter) and the expressed fusion protein in E. coli membranes were catalytically active for nifedipine oxidation, a typical enzymatic activity of P450 3A4. The NADPH-P450 reductase activities of these fusion protein were also determined by measuring reduction of cytochrome c. To fine a specific Inhibitor of P450 3A4 from naturally occurring chemicals, a series of isothiocyanate compounds were evaluated for the inhibitory activity of P450 using the fusion proteins in E. coli membranes. Of the five isothiocyanates (phenethyl isothiocyanate, phenyl isothiocyanate, benzol isothiocyanate, benzoyl isothiocyanate and cyclohexyl isothiocyanate) tested, benzoyl isothiocyanate showed a strong inhibition of P450 3A4 with an $IC_{50}$value of 2.8 $\mu\textrm{M}$. Our results indicate that the self-sufficient fusion protein will be very useful tool to study the drug metabolism and benzyl isothiocyanate may be valuable for characterizing the enzymatic properties of P450 3A4.
Cytochrome P450 2A6 and other human P450 enzymes in the oxidation of flavone and flavanone
Kakimoto, Kensaku,Murayama, Norie,Takenaka, Shigeo,Nagayoshi, Haruna,Lim, Young-Ran,Kim, Vitchan,Kim, Donghak,Yamazaki, Hiroshi,Komori, Masayuki,Guengerich, F. Peter,Shimada, Tsutomu Taylor & Francis 2019 Xenobiotica Vol.49 No.2