Hormonal Regulation of Hepatic Drug Biotransformation and Transport Systems

Abstract

The human body is constantly exposed to many xenobiotics including environmental pollutants, food additives, therapeutic drugs, etc. The liver is considered the primary site for drug metabolism and elimination pathways, consisting in uptake, phase I and II reactions, and efflux processes, usually acting in this same order. Modulation of biotransformation and disposition of drugs of clinical application has important therapeutic and toxicological implications. We here provide a compilation and analysis of relevant, more recent literature reporting hormonal regulation of hepatic drug biotransformation and transport systems. We provide additional information on the effect of hormones that tentatively explain differences between sexes. A brief discussion on discrepancies between experimental models and species, as well as a link between gender-related differences and the hormonal mechanism explaining such differences, is also presented. Finally, we include a comment on the pathophysiological, toxicological, and pharmacological relevance of these regulations.

Potential of plant polyphenols to combat oxidative stress and inflammatory processes in farm animals

“…This is a significant limitation for the ability to translate results from cell culture studies, in which incubations were performed only with the parent compounds, to the in vivo situation. Moreover, it has to be pointed that there are large sex‐related (Mugford and Kedderis, ; Renaud et al., ; Liu et al., ; Ruiz et al., ; Dellinger et al., ; Prokopec et al., ) and species‐dependent (Matal et al., ; Yamazaki et al., ; Helke and Swindle, ; Saengtienchai et al., ) differences in xenobiotic metabolism which largely explains that the spectrum of polyphenol metabolites, their tissue distribution and concentrations in blood following ingestion of polyphenols or polyphenol mixtures can differ markedly between species and between males and females (Weinert et al., ; Margalef et al., ). This is a clear hindrance for the ability to transfer data from male‐to‐female animals and from one species to another one.…”

Drug Transporter Expression and Activity in Human Hepatoma HuH-7 Cells

“…In addition, some sinusoidal ABC transporters mediate transport back of drugs or drug metabolites into the blood, for a secondary renal elimination [ 3 ]. Modulation of hepatic drug transporter expression or activity, which may occur in response to drug treatment or to various physiological or pathological factors [ 4 , 5 , 6 , 7 , 8 ], is thus susceptible to alter pharmacokinetics of drugs in a major way and to lead to drug-drug interactions [ 9 , 10 , 11 ]. Analysis of potential interactions of new drugs with some hepatic transporters is consequently now recommended by drug regulatory agencies [ 12 ].…”

Hepatic Long Intergenic Noncoding RNAs: High Promoter Conservation and Dynamic, Sex-Dependent Transcriptional Regulation by Growth Hormone

“…Liver gene expression is highly responsive to many drugs and environmental chemicals (34,35), which activate nuclear receptor master regulators of hepatic drug and fatty acid metabolism, such as CAR and PXR (36)(37)(38). Hormonal factors also induce large changes in gene expression in the liver (39,40), in particular, expression of genes showing sex-differential expression (31,41), as is also seen in several other nonreproductive tissues (42)(43)(44). In the liver, sex-biased gene expression is regulated by the sex-dependent patterns of pituitary growth hormone (GH) release (39): pulsatile GH release in males versus persistent (nearly continuous) GH release in females (45)(46)(47).…”