Title:Extrahepatic Targets and Cellular Reactivity of Drug Metabolites
Volume: 22
Issue: 4
Author(s): Hilmi Orhan
Affiliation:
Keywords:
Clozapine, drug metabolism, idiosyncratic adverse drug reaction, mitochondria, reactive metabolite, target organ.
Abstract: Biotransformation is one of the key elements of chemically induced toxicity. Although organisms
have an intrinsic tendency to diminish the harm posed by chemical exposure with or without structural modification
and excretion of the agents (detoxification), this is not always the case; toxification may also occur. The
liver has evolved to be the center of biotransformation from the anatomical, physiological and biochemical
points of view; it is located alongside the stomach and intestine, it receives more than 25% of the cardiac output and it
contains, in general, the richest quantity but also variety of drug metabolizing enzymes. That is why many orally taken
drug-induced toxic effects are seen in the liver. Nevertheless, non-hepatic tissues in the organism are also subjected to
toxic insult. Although several instances have suggested transport of liver-bioactivated reactive metabolites to the target
tissue is responsible, such as monocrotaline-associated lung toxicity, tetraethyl lead- and n-hexane-associated nervous system
toxicity and 2-methoxyethanol-associated testis toxicity, etc. [1], the vast majority of data show local bioactivation in
the target tissue is responsible for the extrahepatic toxic outcome. The impact of extrahepatic bioactivation and toxicity of
drugs can also be seen in cases of drug attrition due to unacceptable toxicity; adverse cardiovascular effects were the
foremost reason for drug withdrawals between 1993 and 2006 [2]. On the other hand, the parent drug and/or its stable metabolite(
s) may also cause adverse effects such as inhibition of transporters, occlusion of bile secretion (cholestasis) and
accumulation in organelles such as mitochondria, causing steatosis in liver and possibly in other organs. However, this review
attempts to summarize only extrahepatic bioactivation of drugs/chemicals and their effects at the cellular and tissue
level. Specifically, it focuses on the two most perfused organs, lung and heart tissue, as well as thyroid, blood, brain, and
skin. Clozapine, a still-in-use drug with severe off-target toxicities (agranulocytosis and cardiovascular toxicity), is investigated
in depth and various drugs are reviewed with a special emphasize on the other mentioned organs.
