Cytochrome p450 in humansEdit
Human cytochrome p450's (hereby referred to as CYP) are primarily membrane associated proteins that are found either in the inner membrane of the mitochondria or the endoplasmic reticulum. CYP's metabolize various endogenous substances, that are those substances that originate from within an organ, tissue or cell, and various exogenous substances, that are those substances that come from the outside of the body. Certain CYP proteins are chemical specific whereas other CYP proteins can metabolize an array of chemicals. These enzymes are present in almost all tissues and play important roles in the synthesis of hormones, cholesterol, and vitamin D. Cytochrome p450 compounds also work to metabolize potentially toxic compounds including drugs and the products of endogenous metabolism in the liver, such a bilirubin.
Humans have 57 genes and over 59 pseudogenes of cytochrome p450 that are divided into 18 different families.
Drug Interaction and MetabolismEdit
Cytochrome P450 is responsible for the biotransformation of several drugs. Six different p450 isozymes, CYP1A, CYP2C19, CYP2C9, CYP2D6, CYP2E1, and CYP3A4, have been identified as the particular isozymes that play important roles in drug metabolism (Nebert et al. 2002). Cytochrome P450 is also important in causing the biotransformation of many drugs via oxidation. Significant inactivation of orally administered drugs is caused by the particular isozyme CYP3A4 located in the gastrointestinal tract. Studies done on this particular enzyme show that the drug- drug and drug- food interactions are in fact becoming more integral in understanding drug research. The major issue with prescribing drugs that share the CYP3A4 pathway can be seen when the drugs that were administered had unmeasured levels. If any of the serum levels in the body reach a toxic state, the toxicity can have serious medical consequences. For example, the drug Posicor was first prescribed as an inhibitor of CYP3A4, but had to be taken off of the market following many reports of serious drug- drug interactions and uncontrolled toxicity levels (Ogu et al. 2004).
RH + O2 + 2H+ + 2e- > ROH + H20
where RH can be one of a large number of possible substrates
The steps in the cycle can be summarized in the following way:
- Substrate binding
- The first reduction
- Oxygen binding
- The second reduction
- Oxygen cleavage
- Product formation
- Product release
- Alessandra: Cytochrome p450: Introduction
- Alessandra: Cytochrome p450: Biological function
- Alessandra: Cytochrome p450: Biosynthesis
- Alessandra: Cytochrome p450: Gene sequence
- Alessandra: Cytochrome p450: Amino acid sequence and composition
- Alessandra: Cytochrome p450: Secondary and tertiary structure
- Alessandra: Cytochrome p450: Domains and structural motifs
- Alessandra: Cytochrome p450: Interactions with macromolecules and small molecules
- Alessandra: Cytochrome p450: Molecular biodiversity and evolution
- Alessandra: Cytochrome p450: Literature overview
- Alessandra: Cytochrome p450: Useful online resources
Cytochrome p450 Wikipedia Article
Nebert, Daniel W., and David W. Russell. “Clinical Importance of Cytochromes P450.” The Lancet 360 (2002):1155-162.Http://toxicology.usu.edu/endnote/clinical-importance-of-the-cytochromes-p450.pdf. Web. 12 Feb. 2014.
Ogu, Chris C., and Jan L. Maxa. “Drug Interactions Due to Cytochrome P450.” Baylor University Medical Center Proceedings 13.4 (2000): 421-23. NCBI. Web. 15 Feb. 2014.