Introduction
It is essential for living systems to control lipophilic molecules, but as mentioned earlier, these molecules can be rather ‘elusive’ to a biological system. Their lipophilicity means that they may be poorly water-soluble and may even become trapped in the first living membrane they encounter. To change the physicochemical structure and properties of these molecules they must be conveyed somehow through a medium that is utterly hostile to them, i.e. a water-based bloodstream, to a place where the biochemical systems of metabolism can physically attack these molecules.
Virtually everything we consume, such as food, drink and drugs that are absorbed by the gut will proceed to the hepatic portal circulation. This will include a wide physicochemical spectrum of drugs, from water-soluble to highly lipophilic agents. Charged or water-soluble agents (if they are absorbed) may pass through the liver into the circulation, followed by filtration by the kidneys and elimination. The most extreme compounds at the end of the lipophilic spectrum will be absorbed with fats in the diet via the lymphatic system and some will be trapped in membranes of the gut. The majority of predominantly lipophilic compounds will eventually enter the liver. As mentioned in the previous topic, the main functional cell concerned with drug metabolism in the liver is the hepatocyte. In the same way that most of us can successfully cook foodstuffs in our kitchens at high temperatures without injury, hepatocytes are physiologically adapted to carry out millions of high-energy, potentially destructive and reactive biochemical processes every second of the day without cell damage occurring. Indeed, it could be argued that hepatocytes have adapted to this function to the point that they are biochemically the most resistant cells to toxicity in the whole body – more of those adaptations later.
In the previous topic it was outlined how the circulation of the liver and gut had evolved to deliver xenobiotics to the hepatocytes. The next task is ‘subcellular’- that is, to route these compounds to the CYPs themselves inside the hepatocytes. To attract and secure highly physicochemically ‘slippery’ and elusive molecules such as lipophilic drugs requires a particular subcellular adaptation in hepatocytes, known as the smooth endplas-mic reticulum (SER; Figure 3.1). You will be aware of the rough endoplasmic reticulum (RER) from biochemistry courses, which resembles an assembly line where ribosomes ‘manufacture’ proteins.
Figure 3.1 Location of CYP enzymes and their REDOX partners, cytochrome b5 and POR (P450 oxidoreductase), in the hepatocyte and how lipophilic species are believed to approach the enzymes’ active site
Regarding the SER, pictures of this organelle’s structure resemble a spaghetti-like mass of tubes. The most lipophilic areas of the SER are the walls, that is, the membranes of these interconnected tubes, rather than the inside (lumen). The drugs/ toxins essentially flow along inside the thickness of the walls of the SER’s tubular structure (Figure 3.1) straight into the path of the CYP monooxygenase system. This is a highly lipophilic environment in a lipid-rich cell within a lipid-rich organ, so in a way, it is a ‘conveyor belt’ along which lipophilic molecules are drawn along once they enter the liver for two reasons. Firstly, their lipophilicity excludes them from the aqueous areas of the cell and secondly, the CYPs metabolize them into more water-soluble agents. This ‘repels’ the metabolites from the SER walls, so they enter the lumen or the cytoplasm, so creating and maintaining a concentration gradient, which causes the lipophilic agents to flow towards the P450s in the first place.
