Cytochrome genetic determinants

Polymorphic metabolism Genetically determined rates of metabolism (fast vs. slow) by selected isozymes of cytochrome P-450 drug-metabolizing enzymes. 

The Relationship Between Genetically Determined Variants of Cytochrome P450 Enzymes and Tobacco Dependence... 

These drug-metabolizing enzymes, such as the cytochrome P450s (CYP), are responsible for the metabolic elimination of most of the drugs currently used in medicine. Genetically determined variability in the function of these enzymes can have a profound effect on drug safety and efficacy. 

Pharmacogenetics involves the impact of genetic variation on drug response. The link between genetically determined variation in drug metabolism enzymes (e.g., cytochrome p450, N-acetyltransferase) and intersubject differences in pharmacokinetics is well established. Likewise, there is an increasing awareness that differences in transporter expression can impact the efficacy and safety of pharmacotherapy. 

Omeprazole is an inhibitor of cytochrome P450 isoenzyme CYP2C19, by which moclobemide is extensively metabolised. Activity of this enzyme is genetically determined with about 5% of Caucasians and up to 20% of Asians being poor metabolisers. Consider also Genetic factors , (p.4). 

With regard to the genetic determinants of the higher-eukaryotic cytochromes, the available data are circumscribed in view of the experimental difficulties. However, a certain parallelism between the higher and lower forms is becoming apparent. Evidence for a nuclear specification of cytochrome c apoprotein comes from the finding that both the mule and the hinny have an equal mixture of the horse and the donkey types of this protein [38]. At position 47, the cytochrome c of the horse contains a threonyl residue, and that of the donkey, a serine. The mule-and-hinny case represents an instance of non-sex-linked Mendelian inheritance without dominance [38]. 

Iron is, as part of several proteins, such as hemoglobin, essential for vertebrates. The element is not available as ion but mostly as the protein ligands transferrin (transport), lactoferrin (milk), and ferritin (storage), and cytochromes (electron transport) (Alexander 1994). Toxicity due to excessive iron absorption caused by genetic abnormalities exists. For the determination of serum Fe a spectrophoto-metric reference procedure exists. Urine Fe can be determined by graphite furnace (GF)-AAS, and tissue iron by GF-AAS and SS-AAS (Alexander 1994 Herber 1994a). Total Iron Binding Capacity is determined by fuUy saturated transferrin with Fe(III), but is nowadays mostly replaced by immunochemical determination of transferrin and ferritin. 

These examples demonstrate that both genetic and environmental factors are involved in determining the activity of this and other cytochrome enzymes. Distinct patterns of genetic polymorphisms exist across ethnic groups and these can be tested and investigated alongside possible environmental and dietary factors that may cause differential expression of these genes. 

---