The liver is a prime location since it receives direct blood supply from the gut, i.e. all the chemicals ingested will travel to the liver after they are absorbed and before they move through the systemic circulation. The liver is also a large and very metabolically active organ, therefore its bulk means it has a high capacity to handle tasks such as clearance of chemicals from the blood. It is quantitatively the most important tissue for P450-mediated metabolism. Thus, localization of drug-metabolizing P450s in the liver and other organs of entry serves to protect other tissues by providing a first line of defense against chemicals entering the body. Water soluble chemicals tend to be easily eliminated by on-specific processes, mainly simple filtration by the kidney.
Lipophilic chemicals like to dissolve in similarly lipophilic environments, such as membranes.
So, again, it is hardly surprising to find P450s localised in a membrane environment. It is believed that they are oriented so that the active site of the enzyme opens towards the membrane, facilitating the chanelling of substrates up to where they can be metabolized. The figure below shows a schematic representation of the organization of drug-metabolizing P450s and their redox partners in the ER membrane. By contrast, cytohrome b5 is anchored by a segment of the C-terminus. For all three proteins, the majority of the protein is located on the cytosolic face of the ER membrane.