The metabolism of xenobiotics by certain extrahepatic organs and its relation to toxicity.

Abstract

Considerable interest has developed in recent years in the bioactivation of xenobiotics in extrahepatic organs and in the accompanying toxic effects in these organs. However, the presence of covalently bound xenobiotic in, for example, kidney, coupled with selective pathologic changes in kidney, is not prima facie evidence for the generation of a toxic chemical species in that target organ. There is now abundant and further accumulating evidence that many reactive intermediates may be formed in liver and that they are sufficiently stable to diffuse back into the venous blood and be distributed to other organs where they may be covalently bound and produce tissue injury. Thus, one must exercise caution in equating high concentrations of covalently bound xenobio­ tics in specific organs and pathologic changes in those organs with in situ activation of the xenobiotic. Williams (1) considered the metabolism of foreign chemical compounds, or xenobiotics, to occur via four chemical mechanisms: namely oxidation, reduc­ tion, and hydrolysis (Phase I reactions); and synthesis (conjugation) (Phase II reactions). Many excellent reviews (2-5) are available that discuss the specific types of reactions included with these categories, and they are not repeated here. It suffices to state that most of the reactions that fall within the scope of this review are oxidative reactions of a special type; in general they are catalyzed by enzyme systems known as monooxygenases or mixed function