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METABOLIC ACTIVATION AS A BASIS FOR ORGAN‐SELECTIVE TOXICITY
Author(s) -
Boyd Michael R.,
Grygiel John J.,
Minchin Rodney F.
Publication year - 1983
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.1983.tb00175.x
Subject(s) - toxicity , metabolism , metabolic pathway , in vivo , drug metabolism , carcinogen , enzyme , drug , chemistry , biology , biochemistry , pharmacology , microbiology and biotechnology , organic chemistry
Historically, the concept of metabolic activation was first forwarded to explain the in vivo activity of certain carcinogenic chemicals that without prior metabolism were chemically inert and biologically inactive. Subsequently, the concept has been extended to explain the effects of many different classes of chemicals causing diverse toxicities. Because of its major role in drug metabolism, the liver is a prominent site for toxic injury by agents requiring metabolic activation. The liver can also be the source of reactive metabolites that damage extrahepatic organs. But, organ selective toxicity can also result from the in situ metabolic activation of foreign chemicals in extrahepatic target tissues such as the lungs and the kidneys. Moreover, extrahepatic tissues generally are much more heterogeneous in cellular composition compared to the liver, and the localization of drug metabolizing enzymes in certain cell populations may result in highly cell selective toxic injury. The significance of metabolic activation and toxicity–and the importance of the particular chemical structure of individual compounds, as well as host factors such as species, age, sex, and pretreatment effects –on target‐organ‐selective toxicity by reactive metabolites are illustrated by studies with various furan derivatives, an important class of environmental chemicals. SUMMARY To conclude this paper, we should simply like to restate the major points we have attempted to illustrate herein: (a) some general concepts concerning the relationships between metabolic activation, reactive intermediates, and toxicity; (b) the potential involvement of metabolic activation both in hepatic and in extrahepatic toxicities; (c) a consideration of chemical/structural factors and host factors (e.g. species, strain, sex, age, pretreatments) affecting target organ selectivity, exemplified by furan compounds; and (d) the importance of cellular specificity for metabolism and toxicity in extrahepatic tissues, as exemplified for pulmonary Clara cells with the pulmonary toxin 4‐ipomeanol.