Steroid hormones and many drugs are inactivated in their passage through the liver by modifications of their chemical structures. The liver has enzymes that convert these nonpolar molecules into more polar (more water-soluble) forms by hy-droxylation (the addition of OH- groups) and by conjugation with highly polar groups such as sulfate and glucuronic acid. Polar derivatives of steroid hormones and drugs are less biologically active and, because of their increased water solubility, are more easily excreted by the kidneys into the urine.
Conjugation of steroid hormones and xenobiotics (foreign chemicals that are biologically active) makes them anionic (negatively charged) and hydrophilic (water-soluble). Thus changed, these compounds can be transported by liver cells into the bile canaliculi by multispecific organic anion transport carriers. These carriers have been cloned and identified as the same type that transports similar molecules into the nephron tubules. Through renal secretion (chapter 17) and secretion into the bile, therefore, these transport carriers help the body to eliminate potentially toxic molecules.
The liver cells contain enzymes for the metabolism of steroid hormones and other endogenous molecules, as well as for the detoxication of such exogenous toxic
Production of the cytochrome P450 enzymes, needed for the hepatic metabolism of lipophilic compounds such as steroid hormones and drugs, is stimulated by the activation of a nuclear receptor. Nuclear receptors bind to particular molecular ligands and then activate specific genes (chapter 11; see fig. 11.7). The particular nuclear receptor that stimulates the production of cytochrome P450 enzymes is known as SXR—for steroid and xenobiotic receptor. A drug that activates SXR, and thereby induces the production of cytochrome P450 enzymes, would thus be expected to increase the hepatic metabolism of many other drugs. This is the mechanism responsible for many drug-drug interactions.
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