Inhibition and induction of drug-metabolizing enzymes are the most frequent and dangerous drug-drug interactions. They are an important cause of serious adverse events that have often resulted in early termination of drug development or withdrawal of drugs from the market. Management of such interactions by dose adjustment in clinical practice is extremely difficult because of the wide interindividual variability in their magnitude. This review examines the genetic, physiological, and environmental factors responsible for this variability, focusing on an important but so far neglected cause of variability, liver functional status. Clinical studies have shown that liver disease causes a reduction in the magnitude of interactions due to enzyme inhibition, which is proportional to the degree of liver function impairment. The effect of liver dysfunction varies quantitatively according to the nature, reversible or irreversible, of the inhibitory interaction. The magnitude of reversible inhibition is more drastically reduced and virtually vanishes in patients with advanced hepatocellular insufficiency. Two mechanisms, in order of importance, are responsible for this reduction: decreased hepatic uptake of the inhibitory drug and reduced enzyme expression. The extent of irreversible inhibitory interactions is only partially reduced, as it is only influenced by the decreased expression of the inhibited enzyme. Thus, for appropriate clinical management of inhibitory drug interactions, both the liver functional status and the mechanism of inhibition must be taken into consideration. Although the inducibility of drug-metabolizing enzymes in liver disease has long been studied, very conflicting results have been obtained, mainly because of methodological differences. Taken together, the results of early animal and human studies indicated that enzyme induction is substantially preserved in compensated liver cirrhosis, whereas no definitive conclusion as to whether it is significantly reduced in the decompensated state of cirrhosis was provided. Since ethical constraints virtually preclude the possibility of performing methodologically rigorous investigations in patients with severe liver dysfunction, studies have recently been performed in animals rigorously stratified according to the severity of liver insufficiency. The results of these studies confirmed that enzyme induction is virtually unaffected in compensated cirrhosis and indicated that the susceptibility of enzyme induction to severe liver dysfunction depends on the type of nuclear receptor involved and also varies among enzyme isoforms under the transcriptional control of the same nuclear receptor. These findings make it clear that no general conclusion can be reached from the study of any particular enzyme and partly explain the conflicting results obtained by previous studies. Since no general guidelines can be provided for the management of drug interactions resulting from enzyme induction, both the effects and the plasma concentration of the induced drug should be strictly monitored. The findings discussed in this review have important methodological implications as they indicate that, contrary to current guidelines, the magnitude of metabolic drug-drug interactions in patients with liver disease cannot be inferred from studies in healthy subjects.

A peculiar role for oxidative stress in non-alcoholic fatty liver disease (NAFLD) and its transition to the inflammatory complication non-alcoholic steatohepatitis (NASH), as well as in its threatening evolution to hepatocellular carcinoma (HCC), is supported by numerous experimental and clinical studies. NADPH oxidases (NOXs) are enzymes producing reactive oxygen species (ROS), whose abundance in liver cells is closely related to inflammation and immune responses. Here, we reviewed recent findings regarding this topic, focusing on the role of NOXs in the different stages of fatty liver disease and describing the current knowledge about their mechanisms of action. We conclude that, although there is a consensus that NOX-produced ROS are toxic in non-neoplastic conditions due to their role in the inflammatory vicious cycle sustaining the transition of NAFLD to NASH, their effect is controversial in the neoplastic transition towards HCC. In this regard, there are indications of a differential effect of NOX isoforms, since NOX1 and NOX2 play a detrimental role, whereas increased NOX4 expression appears to be correlated with better HCC prognosis in some studies. Further studies are needed to fully unravel the mechanisms of action of NOXs and their relationships with the signaling pathways modulating steatosis and liver cancer development.

Non-alcoholic fatty liver disease (NAFLD) and its complication non-alcoholic steatohepatitis (NASH) are important causes of liver disease worldwide. Recently, a significant association between these hepatic diseases and different central nervous system (CNS) disorders has been observed in an increasing number of patients. NAFLD-related CNS dysfunctions include cognitive impairment, hippocampal-dependent memory impairment, and mood imbalances (in particular, depression and anxiety). This review aims at summarizing the main correlations observed between NAFLD development and these CNS dysfunctions, focusing on the studies investigating the mechanism(s) involved in this association. Growing evidences point at cerebrovascular alteration, neuroinflammation, and brain insulin resistance as NAFLD/NASH-related CNS manifestations. Since the pharmacological options available for the management of these conditions are still limited, further studies are needed to unravel the mechanism(s) of NAFLD/NASH and their central manifestations and identify effective pharmacological targets.