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module B - Enzymatic and toxicological properties of the...

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Enzymatic and toxicological properties of the cytochrome P450 isoforms Each isoform within the p450 family has a certain substrate preference (some prefer things with benzene rings and some don’t), the individual molecular structure of the xeniocbitoic will often determine which of the P450 isoforms would have preference and oxidize a particular xeniobotioc , these isoforms are rather broad and not entirely specific Another level of complication is that within each CYP isoform, most of these families are inducible the level of the enzyme will be quite low (may be undetectable), because the gene that codes for that particular isoform is relevantly inactive, it is not synthesising much mRNA and therefore the level of protein synthesis from that mRNA is also correspondingly low On the other hand, these genes are also regulated by various environmental factors and cellular factors as well. So under certain circumstances you may find that there is a dramatic up regulation and induction of the cyclic form, because usually there is a xenobiotic that has come into the liver or other tissues in the body, its been recognized as something that should be oxidized by a particular CYP isoform and correspondingly would be an induction of genetic up regulation that will allow the tissue to adapt to the xenobiotic, by making more CYP and therefore allowing a greater level of degradation. This system will be different from individual to individual – genetic, diet etc. o All these food, drug or environmental related factors will interact NADPH-P450 reductase-cytochrome P450 oxidative and reductive pathways The P450 can also undertake reduction reactions and these reduction reactions are much less common, so its relatively a minor pathway, but reduction pathway occur when the substrate has relatively few oxygen’s. So of the nitrogen centre, substrates that are metabolized by P450. These are reactions that are the opposite of oxidation, but nonetheless it’s the energy within the P450 system that is driving that reaction, even though tis the flip side of the normal reaction. We’re going to look mostly at oxidative pathways Cytochrome P450(CYP) genetic superfamily Now if you look at the human liver, what you might find is that there are number of different p450 and this is a pie chart showing relative abundance of the major p450 isotopes, in a liver. The major member is 1A2 isoform, 20% of central; another one is major of 2 family is 2E1 (involved in xenobiotic metabolism), another one is 2C, 2D6 and 2A6 (involved in metabolism of particular drugs, most specifically metabolism of nicotine) is major nicotine pathway, often found in ppl who are more prone to cigarette addiction carry different 2D6 polymorphism that ppl who are less prone to have a cigarette addiction. So these are not only involved in xenobiotic metabolism, but may also have bio-behavioural roles. 3A4 major family of 3, it has
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broad specificity, tends to oxidize a lot of xenobiotics and oxides quite a few pharmaceutical drugs
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