Xenobiotics and Hepatotoxicity
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Most drugs and xenobiotics are lipophilic, enabling them to cross the membranes of intestinal cells.
- At least six mechanisms that primarily involve the hepatocyte produce liver injury, and the manner in which various intracellular organelles are affected defines the pattern of disease.
| Disruption of the hepatocyte | Covalent binding of the drug to intracellular proteins ---»decrease in ATP levels---» actin disruption the surface of the hepatocyte --» blebs and rupture of the membrane. |
| Disruption of the transport proteins | Drugs that affect transport proteins at the canalicular membrane ---» interrupt bile flow---» Loss of villous processes and interruption of transport pumps such as multidrug resistance–associated protein 3 ---»prevent the excretion of bilirubin---» cholestasis. |
| Cytolytic T-cell activation | Covalent binding of a drug to the P-450 enzyme acts as an immunogen---»activating T cells and cytokines ---»stimulating a multifaceted immune response. |
| Apoptosis of hepatocytes | Activation of the apoptotic pathways by the tumor necrosis factor-alpha receptor of Fas ---»trigger the cascade of intercellular caspases---»programmed cell death. |
| Mitochondrial disruption | Certain drugs inhibit mitochondrial function by a dual effect on both beta-oxidation energy production by inhibiting the synthesis of nicotinamide adenine dinucleotide and flavin adenine dinucleotide, ---»decreased ATP production. |
| Bile duct injury | Toxic metabolites excreted in bile ---»injury to the bile duct epithelium. |
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