Liver Metabolism of Foreign Compounds

The liver has gained popularity over the years among the alternative health space. Many label the liver as the most important detoxification organ in the human body. Although the claim holds significance, it is not to undermine the role of other organs like the kidneys, intestines & lungs which work in collaboration with the liver to aid in detoxification. So how exactly does the liver metabolize foreign compounds out of the body?

The detoxification process begins with a concept referred to as Biotransformation, which is the metabolism of Lipophilic (fat soluble) Xenobiotic (foreign) molecules into more Hydrophilic (water soluble) molecules. In the middle of the 20th century, R. T. Williams proposed the phasic sequence of drug metabolism: Phase 1 followed by a Phase 2. In Phase 1, a drug or xenobiotic molecule is either activated or inactivated typically by a family of enzymes called Cytochrome P450 (CYPs) through one of the three types of permanent chemical biotransformations: Oxidation, Reduction or Hydrolysis. Phase 2 conjugates (combines) the metabolites produced in Phase 1 to Glucuronate, Sulfate, Acetate esters or Glutathione for simpler secretion into blood or bile. Phase 2 may be performed independent of Phase 1. (I will go into more detail on Phases 1 & 2 in my next article) The type of xenobiotic determines the reaction necessary to detox. (Josephy et al. 2005) recorded the class of reactions as such:

• Oxidative reactions that are catalyzed by Cytochromes P450 (CYPs), Monoamine Oxidases (MAOs), Peroxidases, Xanthine Oxidase (XO), or Alcohol Dehydrogenase

• Reductive reactions that typically involve either Azo or Nitro-reductions

• Conjugation reactions in which electrophilic Adenosine-containing cofactors such as ATP, Phosphoadenosine Phosphosulfate (PAPS), Acetylcoenzyme A (acetylCoA), Uridine Diphosphate Glucuronic acid (UDPGA), or S-adenosylmethionine (SAM) react with nucleophilic groups such as –OH or –NH2

• Nucleophilic trapping in which water, Glutathione, or other nucleophiles react with electrophiles

Sources:

Hacker, M.P., Messer, W.S. and Bachmann, K.A. (2009) “Chapter 8 - Drug Metabolism ,” in Pharmacology: Principles and practice. Amsterdam: Elsevier/Academic Press, pp. 131–173.

Josephy, D., Guegerich, F. P., & Miners, J. O. (2005). Phase I and Phase II drug metabolism: Terminology that we should phase out? Drug Metabolism Reviews, 37, 575–580.