Cytochrome lipophilic interaction

As in vitro methods for studying cytochrome P-450 in insects became available (11-131, it soon became clear that insects with high cytochrome P-450 activities were resistant to carbamates and most other insecticides. This phenomenon is termed metabolic cross resistance and derives from the characteristic of cytochrome P-450 of accepting a very wide range of molecular structures as substrates the cytochrome binds the substrate very loosely by a lipophilic interaction and rapidly oxidizes it by an oxygen free radical-mediated reaction, a very powerful combination. Moreover, the cytochrome occurs in several or many different isoenzymic forms with broadly overlapping substrate preferences. A normally infrequent form may be selectively induced by allelochemicals in the crop plants (14), and if the induced form has survival value in the presence of an insecticide, it could be selected to dominate in the exposed population (15). 

Lewis, D. F., Lake, B. G., Ito, Y., Anzenbacher, P. Quantitative structure-activity relationships (QSARs) within cytochromes P450 2B (CYP2B) subfamily enzymes the importance of lipophilicity for binding and metabolism. Drug Metab. Drug Interact. 

DNA can also be a target for alkaloids planar and lipophilic alkaloids, such as berberine and sanguinarine (Figure 1.6) are intercalating compounds that assemble between the stacks of paired nucleotides in the DNA double helix [2,3,18,23]. DNA intercalation can disturb replication, DNA repair, and DNA topoisomerases. Frameshift mutations are one of the adverse consequences of intercalating compounds. Some alkaloids, such as pyrrolizidine alkaloids, aristolochic acids, cycasin, and furoquinoline alkaloids, are known to form covalent adducts with DNA bases. Mutations and tumor formation can be the result of such interactions. DNA alkylation occurs in some alkaloids only after activation by liver enzymes, such as cytochrome p450 oxidases (pyrrolizidine alkaloids, aristolochic acids) [17,18,24]. 

Humans are exposed continuously and unavoidably to a myriad of potentially toxic chemicals that are inherently lipophilic and, consequently, very difficult to excrete. To effect their elimination, the human body has developed appropriate enzyme systems that can transform metabolically these chemicals to hydrophilic, readily excretable, metabolites. This biotransformation process occurs in two distinct phases. Phase I and Phase II, and involves several enzyme systems, the most important being the cytochromes P450. The expression of these enzyme systems is regulated genetically but can be modulated also other factors, such as exposure to chemicals that can either increase or impair activity. Paradoxically, the same xenobiotic-metabolizing enzyme systems also can convert biologically inactive chemicals to highly reactive intermediates that interact with vital cellular macromolecules and elicit various forms of toxicity. Thus, xenobiotic metabolism does not always lead to deactivation but can result also in metabolic activation with deleterious consequences. 

Figure 40 Molecular surface of the substrate channel of a cytochrome F-450 protein. The surface is color coded according to the lipophilic potential (blue = almost hydrophilic, brown = almost lipophilic). The left figure shows the complete channel surface as solid model. The atoms forming the channel are represented as wire frame. The small barrel and the small cone are so-called space buttons used for the implementation of interactivity. The barrel leads to a HTML document giving a short description of the scene. By clicking on the cone the quality of the surface is reduced to chicken-wire representation. Also the color ramp, here called space ramp , is linked to other VRML files. The result of a click to the hydrophilic part is shown on the right. All parts of the surface remaining under a defined threshold of lipophilicity are removed...

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