Classification of the CYP450 Multigene Family

There are 57 different CYP450s.  52 of these are located in the smooth ER and are known as microsomes.  When naming the cytochromes they all have a numerical family name, alphabetical subfamily name, and numerical gene name.  CYP3A and CYP2C are the isoforms that are most responsible for metabolism of drugs.  The CYP3A4 and CYP3A5 account for 37% of the P450s that metabolize drugs in the liver.  CYP2C8 and CYP2C9 account for 17%, CYP2C18 and CYP2C19 account for 8%, and CYP2D6 accounts for 21%.  Other important cytochromes are CYP1A2 which metabolizes environmental compounds and CYP21 which metabolizes small molecules such as ethanol, anesthetics, and small organic solvents.  All CYP450s have non-specific binding sites and the only difference in them are the amino acids that you find in the pocket of the active site.

The 1A family of CYP450 is important for metabolizing two classes of environmental carcinogens, polycyclic aromatic hydrocarbons, and aryl amines.  Both carcinogens can be found in burnt meat.  CYP1A1 serves as an aromatic hydrocarbon hydroxylase.  It is primarily expressed in the extrahepatic tissue.  CYP1A2 is similar but it is found in the liver, stomach, and intestines.  Both CYP450s are inducible and provide inter-individual variation.

CYP2A6 are found in the liver, lungs and nasal epithelium.  They metabolize drugs like coumarin, procarcinogens, and nicotine.  These enzymes are known to have polymorphism.  CYP2C is composed of CYP2C8 that is found in the liver and skin, CYP2C9 that is found primarily in the liver and intestine, and CYP2C19 that is primarily found in the liver and intestine.  The CYP2C family metabolizes 25% of the clinically important drugs and represents 20% of the total CYP450 isozymes in the liver.  They are also known to have polymorphisms.  CYP2D6 have polymorphism and metabolize 21% of the clinically important drugs.  They represents 3% of the total CYP450 isozymes in the liver.  They do not appear to be inducible and their preferred substrates are lipophilic amines.  CYP2E1 have minimal drugs that are metabolized by this CYP450 isoform.  It is expressed in liver, kidney, intestine and lung.  It is inducible by alcohol, diet, and diabetes.  It also has a polymorphism in Chinese people.

CYP3A4 is the most abundant liver CYP450 isoform (34%).  They are expressed in liver,intestine, lung, kidney, brain, uterus, and placenta.  They are responsible for 33% of the clinically important drugs.  They are inducible but they are inhibited by the antibiotic erythromycin.  It also likes lipophilic drugs and they activate aflatoxin B1 (fungal metabolite that grows on peanuts).

Induction is when you increase the amount of CYP450 protein which leads to greater activity.  The consequence of induction is that you will alter the pharmacokinetics and pharmacodynamics of certain drugs.  Self-induction may occur as well.  Ethanol is a self inducer of CYP2E1 for example.   Phenobarbital is an inducer of CYP450 As well as rifampin, cigarette smoke, brussels sprouts, cabbage, cauliflower, and alcohol. Rifampin and St. Johns Wort increase metabolism of oral contraceptives which leads to decreased blood levels and effectiveness. Rifampin and St. Johns Wort can also increase the metabolism of endogenous compounds as well as enhance activation of procarcinogens.

Inhibition decreases CYP450 activity.  There are two types of inhibition that occur based on covalent bonding.  Reversible inhibition agents include; fluoroquniolones, cimetidine, antifungals, and quinidine.  Irreversible inhibitions include; macrolide antibiotics (such as troleandomycin, erythromycin, clarithromycin), chloramphenicol, cyclophosphamide, and spironolactone.

Single nucleotide polymorphism substitutions (SNPs) are a type of polymorphism.  There can be a coding nonsynonymous SNP - change in nucleotide sequence with a change in amino acid composition which alters the protein.  You will see a change in activity or affinity. 2) Coding synonymous – change in nucleotide sequence with no change in amino acid sequence.  Yo get the same protein but changing the nucleotide will change the half-life of the message. 3) Noncoding – change in nucleotide sequence. or a change in the promoter.

Indels (insertion/deletions) are polymorphisms that have the same effects as SNPs.  You may see short repeats of genes, larger gene deletions, or larger gene insertions.  You may also see gene deletions and gene duplications.