肝外靶点和药物代谢物的细胞反应性

Title:Extrahepatic Targets and Cellular Reactivity of Drug Metabolites

Volume: 22 Issue: 4

Author(s): Hilmi Orhan

Affiliation:

关键词: 氯氮平，药物代谢，特殊的药物不良反应，线粒体，活性代谢物，靶器官

摘要: 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.

Cite this article as:

Hilmi Orhan , Extrahepatic Targets and Cellular Reactivity of Drug Metabolites, Current Medicinal Chemistry 2015; 22 (4) . https://dx.doi.org/10.2174/0929867321666140826113716