Chemical toxicology: reactive intermediates and their role in pharmacology and toxicology

被引:52
作者
Erve, John C. L. [1 ]
机构
[1] Wyeth Ayerst Res, Drug Safety & Metab, Collegeville, PA 19426 USA
关键词
drug action; drug toxicity; idiosyncratic toxicity; protein binding; reactive intermediates;
D O I
10.1517/17425255.2.6.923
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Reactive intermediates formed during the metabolism of drugs have been investigated extensively over the past decades. Today, interest in reactive intermediates in drug discovery is focused on minimising bioactivation in hopes of reducing the risk of causing so-called idiosyncratic toxicity. These efforts are justified based on the 'hapten hypothesis', namely, that on binding to protein, reactive intermediates may elicit an immune response to the modified protein, leading to a cascade of events that ultimately manifests as a toxic outcome. However, the pharmacological action of certain drugs depends on reactive intermediates that modify critical amino acid residues of proteins, typically enzymes, thereby altering their activity. Thus, the notion that reactive intermediates are inherently dangerous is unjustified. When a reactive intermediate is necessary for the desired pharmacological effect of a drug, the selectivity it displays towards the target protein is crucial, as off-target binding may produce unwanted toxicities. On the other hand, reactive intermediates may play no role in toxicity. This review provides a balanced perspective, primarily focusing on the proposed role of reactive intermediates in drug toxicity, while also highlighting examples in which they are involved in causing the desired pharmacology. It is hoped that this knowledge can help scientists involved in drug discovery and development in their challenging task of producing safe and effective drugs.
引用
收藏
页码:923 / 946
页数:24
相关论文
共 153 条
  • [71] A comprehensive listing of bioactivation pathways of organic functional groups
    Kalgutkar, AS
    Gardner, I
    Obach, RS
    Shaffer, CL
    Callegari, E
    Henne, KR
    Mutlib, AE
    Dalvie, DK
    Lee, JS
    Nakai, Y
    O'Donnell, JP
    Boer, J
    Harriman, SP
    [J]. CURRENT DRUG METABOLISM, 2005, 6 (03) : 161 - 225
  • [72] Reactivity of atropaldehyde, a felbamate metabolite in human liver tissue in vitro
    Kapetanovic, IM
    Torchin, CD
    Strong, JM
    Yonekawa, WD
    Lu, C
    Li, AP
    Dieckhaus, CM
    Santos, WL
    Macdonald, TL
    Sofia, RD
    Kupferberg, HJ
    [J]. CHEMICO-BIOLOGICAL INTERACTIONS, 2002, 142 (1-2) : 119 - 134
  • [73] Protection of dopaminergic neurons with a novel astrocyte modulating agent (R)-(-)-2-propyloctanoic acid (ONO-2506) in an MPTP-mouse model of Parkinson's disease
    Kato, H
    Araki, T
    Imia, Y
    Takahashi, A
    Itoyama, Y
    [J]. JOURNAL OF THE NEUROLOGICAL SCIENCES, 2003, 208 (1-2) : 9 - 15
  • [74] THE ORGAN TOXICITY OF INHALED ANESTHETICS
    KENNA, JG
    JONES, RM
    [J]. ANESTHESIA AND ANALGESIA, 1995, 81 (06) : S51 - S66
  • [75] A COMPARATIVE-STUDY OF THE FORMATION OF CHEMICALLY REACTIVE DRUG METABOLITES BY HUMAN-LIVER MICROSOMES
    KITTERINGHAM, NR
    LAMBERT, C
    MAGGS, JL
    COLBERT, J
    PARK, BK
    [J]. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1988, 26 (01) : 13 - 21
  • [76] Identification of seven proteins in the endoplasmic reticulum as targets for reactive metabolites of bromobenzene
    Koen, YM
    Hanzlik, RP
    [J]. CHEMICAL RESEARCH IN TOXICOLOGY, 2002, 15 (05) : 699 - 706
  • [77] Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib
    Kwak, EL
    Sordella, R
    Bell, DW
    Godin-Heymann, N
    Okimoto, RA
    Brannigan, BW
    Harris, PL
    Driscoll, DR
    Fidias, P
    Lynch, TJ
    Rabindran, SK
    McGinnis, JP
    Wissner, A
    Sharma, SV
    Isselbacher, KJ
    Settleman, J
    Haber, DA
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (21) : 7665 - 7670
  • [78] LAIDLAW ST, 1993, LANCET, V342, P1245
  • [79] Studies on the sensitization of animals with simple chemical compounds
    Landsteiner, K
    Jacobs, J
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1935, 61 (05) : 643 - U8
  • [80] Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase
    Learmonth, DA
    Vieira-Coelho, MA
    Benes, J
    Alves, PC
    Borges, N
    Freitas, AP
    Soares-Da-Silva, P
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (03) : 685 - 695