Cytochrome P450 liver enzymes transporter

From the above, it is clear that the gut wall represents more than just a physical barrier to oral drug absorption. In addition to the requirement to permeate the membrane of the enterocyte, the drug must avoid metabolism by the enzymes present in the gut wall cell as well as counter-absorptive efflux by transport proteins in the gut wall cell membrane. Metabolic enzymes expressed by the enterocyte include the cytochrome P450, glucuronyltransferases, sulfotransferases and esterases. The levels of expression of these enzymes in the small intestine can approach that of the liver. The most well-studied efflux transporter expressed by the enterocyte is P-gp. 

All tissues except mature red blood cells are able to manufacture haem for use in the respiratory cytochrome proteins of the electron transport chain. However, the liver is an especially important site of haem synthesis because it (a) is a major organ of erythropoiesis in utero and (b) haem-containing cytochrome-P450 (CYP-450) enzymes play significant roles in hepatic detoxification of drugs, toxins and endogenous waste products (Section 6.4). 

The precursor, 7-dehydrocholesterol is converted by a non-enzymatic reaction to cholecalciferol (calciol). This reaction occurs in skin exposed to sunlight due to irradiation by UV-B light at a wavelength of about 300 nm. Cholecalciferol is transported via carrier proteins to the liver where hydroxylation at carbon-25 occurs in a reaction catalysed by a microsomal cytochrome P450 hydroxylase to form calcidiol. This compound travels to the kidney attached to specific binding proteins, where another cytochrome P450 enzyme, mitochondrial 1-a-hydroxylase, introduces a second hydroxyl group in to the molecule to form the active calcitriol. 

It should be noted that the genetic information for the P450 enzymes is present throughout in all tissues, but knowledge of the role of the enzymes in tissues other than the liver and gastrointestinal tract is unclear. For example, cytochrome P450 2D6 is found in the brain where it is linked to the dopamine transporter. Whether a deficit in the activity of this enzyme is responsible for predisposing some individuals to Parkinson s disease is a matter of conjecture. 

NO also has cytotoxic effects when synthesized in large quantities, eg, by activated macrophages. For example, NO inhibits metalloproteins involved in cellular respiration, such as the citric acid cycle enzyme aconitase and the electron transport chain protein cytochrome oxidase. Inhibition of the heme-containing cytochrome P450 enzymes by NO is a major pathogenic mechanism in inflammatory liver disease. 

Significant differences in the equilibrium constants for carbon monoxide binding to cytochromes P450 from bacterial, liver microsomal, and adrenal cortex microsomal sources, different isozymes of the liver microsomal proteins, and for substrate-free and substrate-bound enzymes, have been observed and have been related to similar factors that affect O2 and CO binding in oxygen transport and storage heme proteins. The importance of the cis and tmns effects, that is electronic effects associated with the porphyrin... 

After oral administration, carbamazepine is slowly but erratically absorbed with wide individual variability. Over 80% of the drug is protein bound.. The elimination half-life early in therapy is approximately 24 hours. With chronic therapy, the enzyme cytochrome P450 3A4 (CyP 3A4) and its associated drug transporter P-glycoprotein (Pg)— responsible for metabolism— are induced, and the elimination half-life is reduced to 15 to 20 hours. Because hepatic metabolism is the principal means by which plasma concentration is reduced, any reduction in liver function results in drug accumulation. 

Although it is unclear why this is so, it can be speculated that administration of AEDs increases the expression of drug transporters not only in the immediate environment of the epileptic foci but also in other organs, including the liver and kidneys. In conjunction with cytochrome P450 enzyme expression in the liver, this would lead to both degradation and excretion of AEDs. It is also plausible that endocrine factors released into the blood stream in the course of a seizure may be directed toward organs such as the BBB, the kidneys, and the liver, but not the luminal side of the gut. 

Cholestasis is a condition characterized by impaired flow of bile, due to physical obstruction of the biliary tree or decreased bile secretion by the liver. Cholestasis produces alterations of enzyme activity in the liver (cytochrome P450) as well as altered transporter expression, with associated effects on drug clearance. As discussed previously, cholestasis can occur through inhibition of the canalicular membrane transporter, BSEP. In response to cholestasis, however, the liver has adaptive mechanisms to minimize cellular accumulation of toxic bile salts. These include upregulation of MRP3 to increase sinusoidal efflux, and downregulation of Na -taurocholate cotransporting polypeptide (NTCP), which mediates bile salt uptake from the blood to the liver. 

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