Title:Mitochondrial Biotransformation of Drugs and other Xenobiotics
Volume: 22
Issue: 8
Author(s): Hilmi Orhan*, Fuat Karakuş and Ali Ergüç
Affiliation:
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ege University, Bornova-Izmir 35040,Turkey
Keywords:
Mitochondria, biotransformation, xenobiotic-metabolizing enzymes, bioactivation, clozapine, paracetamol.
Abstract: In vivo biotransformation of exposed chemicals is one of the major factors that determine the concentration
and the duration of a substance at the systemic site of effect. Given that toxicity is expressed as a function of two
factors, namely dose and time, the type and intensity of the toxicity are directly dependent on the chemical transformation
of the exposed parent substance. This dependency involves two different situations. The amount of the
chemical reaching the target will be decreased with the extent of metabolism if the parent chemical is toxic, and the
opposite is true if the metabolite(s) is toxic instead. To date, the liver microsomal fraction in mammals has been
justifiably considered as the center of biotransformation reactions because the liver and microsomes (i.e., endoplasmic
reticulum component of the cell) possess the most abundant types and quantities of xenobiotic-metabolizing
enzymes, especially the cytochrome P450 supergene enzyme family. These enzymes are common in all kingdoms of
life, which strongly suggests that the origin of life is common. It is already known that various drugs enter mitochondria
by different mechanisms, and this translocation is believed to be responsible for mitochondrial effects that are
part of the therapeutic actions of various drugs such as lipid-lowering statins or antidiabetogenic thiazolidindiones.
However, the discovery of mitochondrial forms of the xenobiotic-metabolizing enzymes provoked discussions about
whether mitochondria metabolize drugs and other chemicals to some extent. This possibility may particularly be
important as mitochondria have various critical cellular structures and functions. In the case of in situ generated
metabolite(s), when there are adverse interactions with either these structures or functions, various toxic outcomes
may appear. In this review, we compiled studies in the literature regarding biotransformation of drugs and other
chemicals catalyzed by mitochondria where it is both an initiator and target of toxicity.
