Cytochrome P450 isoenzymes (CYPs)
- Cytochrome P450 enzyme isoforms and their therapeutic implications: An update
Cytochrome P450 isoenzymes (CYPs)
The Cytochrome P450 isoenzymes (CYPs) are superfamily of haemoprotein enzymes found on the membrane of endoplasmic reticulum. They are responsible for catalyzing the metabolism of large number of endogenous and exogenous compounds. CYPs are also known as mixed function oxidases and mono-oxygenases as metabolism of a substrate by a CYP consumes one molecule of molecular oxygen and produces an oxidized substrate and another molecule of oxygen appears in water as byproduct. CYPs are also called polysubstrate mono-oxygenases as one isoenzyme can have multiple substrates., These enzymes are responsible for biotransformation of drugs and are body's defense against xenobiotics along with P-glycoprotein. P-glycoprotein is efflux pump or transporter present in brain capillary endothelial cells, intestinal mucosal, renal and tubular cells, hepatic canalicular cells etc and are responsible for extrusion or efflux of drugs thereby enhancing drug elimination.
Cytochrome P450 isoenzymes are predominantly present in liver but are also found in intestine, lungs, kidneys, brain etc. Biotransformation of drugs by these enzymes render them ionic and more water soluble so that they can be excreted, drawback of this process is limited bioavailability of drugs. CYPs catalyse variety of reactions including N-dealkylation, O-dealkylation, S-oxidation, epoxidation and hydroxylation. A typical CY P450 catalysed reaction:
NADPH + H+ + O 2 + RH g NADP+ + H 2 O + R-OH
RH denotes parent drug and R-OH is oxidized product[Figure - 1].
Other oxidative enzymes such as dehydrogenases and flavin containing monooxygenases (FMOs) also are capable of catalyzing the metabolism of specific drugs, but, in general such enzymes are of minor overall importance.
Cytochrome P450 isoenzymes are designated by the letters e.g., CYP2D 6 , "CYP followed by an Arabic numeral, a letter and another Arabic numeral (italics). 'P' in cytochrome P450 stands for 'pigment'. Each enzyme is termed as isoform since each is derived from a different gene. These isoforms have a spectrophotometric absorption peak at or near 450 nm when bound and reduced by carbon monoxide., Cytochrome P450 isoenzymes nomenclature based on the presence of common amino acid sequence was proposed by Nebert and colleagues;
Families - proteins with at least 40% amino acid sequence homology. In humans upto 21 families have been described. e.g., CYP2, CYP3.
Subfamilies - members of the same family must have at least 55% amino acid sequence homology. e.g., CYP2D, CYP3A.
Individual genes - they are denoted by Arabic numeral (italics), there are 50 or so genes important in man. e.g., CYP2D 6 , CYP3A 4.
In humans upto 21 families, 20 subfamilies and 57 genes have been described. Out of these CYP 1, 2 and 3 account for 70% of total hepatic CYPs content and are responsible for 94% of drugs metabolism in liver. To identify which P450 isozymes are responsible for metabolizing drugs, several in vitro approaches have been developed. Some of these approaches include: (a) metabolism by microsome derived from cDNA-expressed enzyme, (b) use of selective inhibitors with microsomes, (c) Immunoinhibition of CYP by isoforms specific anti-P450 antibodies in microsomes and (d) correlation of drug candidate metabolites formation with several isoform specific P450 activities in a panel of liver microsomes. A combination of approaches is typically required to accurately identify which P450 isoenzyme is responsible for metabolizing a drug. However, the use of cDNA expressed P450s for the preliminary determination of the principal CYPs involved in a drug candidate's metabolism is a reasonable starting point in a drug discovery setting.
Drug interactions involving the CYP isoforms generally result from one or two processes, enzyme induction or enzyme inhibition. Enzyme inhibition usually involves competition from another drug for enzyme binding site. This process usually begins with the first dose of the CYP inhibitor. Thus, this review is an attempt to briefly summarize the current understanding of CYP isoforms and various drug interactions resulting from drugs metabolized by these isoenzymes, also this review provides hands on information on drug interactions faced by clinicians in routine practice.
Clinically important aspects of CYP450 drug metabolism:
- Genetic polymorphism
- Drug- Drug interaction
A) Enzyme induction
B) Enzyme inhibition
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