Metabolic activation as a basis for organ-selective toxicity.

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.