Abstract
1-Aminobenzotriazole (1-ABT) is a pan-specific, mechanism-based inactivator of the xenobiotic metabolizing forms of cytochrome P450 in animals, plants, insects, and microorganisms. It has been widely used to investigate the biological roles of cytochrome P450 enzymes, their participation in the metabolism of both endobiotics and xenobiotics, and their contributions to the metabolism-dependent toxicity of drugs and chemicals. This review is a comprehensive evaluation of the chemistry, discovery, and use of 1-aminobenzotriazole in these contexts from its introduction in 1981 to the present.
Highlights
The inhibition of cytochrome P450 enzymes to study their roles in the metabolism of endogenous compounds and xenobiotics, and for potential practical purposes, began as soon as this class of enzymes was recognized in the early 1960s [1]
With increasing understanding of the native complement of cytochrome P450 enzymes in humans and other species, the understanding provided by genomic data, the search for cytochrome P450 inhibitors diverged into two tracks
Agents have been sought that are pan-specific, i.e., that broadly inhibit the complement of cytochrome P450 enzymes involved in drug metabolism, while minimally perturbing the P450 enzymes involved in biosynthetic processes
Summary
The inhibition of cytochrome P450 enzymes to study their roles in the metabolism of endogenous compounds and xenobiotics, and for potential practical purposes, began as soon as this class of enzymes was recognized in the early 1960s [1]. A daily 50 mg/kg injection of 1-ABT to rats over five days greatly lowered the urinary excretion of 20-HETE and the ability of renal cortical microsomes to oxidize arachidonic acid to 20-HETE and epoxyeicosatrienoic acids [150,151,152] These examples are part of an extensive body of data (Table 4) indicating that 1-ABT is a mechanism-based cytochrome P450 inactivating agent of the enzymes that oxidize arachidonic acid to its diverse metabolites. Classical P450 inhibitors such as SKF-525A did not attenuate pulmonary thymidine incorporation, a marker of tissue injury, associated with administration of cyclophosphamide, whereas pretreatment with 1-ABT lowered thymidine incorporation into lung DNA on days 3 and 10, but not on day 7 Agents, such as indomethacin and aspirin, which inhibit arachidonic acid pathways independent of cytochrome P450, reduced levels of thymidine incorporation in the lung. These behavioral changes were prevented by pretreatment with 1-ABT, implicating oxidative metabolism of this substrate in its deleterious effects [247]. 1-ABT decreased the mortality and vestibular toxicity of allylnitrile [248]
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