Hypoalbuminemia affects the spatio-temporal tissue distribution of ochratoxin A in liver and kidneys: consequences for organ toxicity

Abstract

Hypoalbuminemia (HA) is frequently observed in systemic inflammatory diseases and in liver disease. However, the influence of HA on the pharmacokinetics and toxicity of compounds with high plasma albumin binding remained insufficiently studied. The ‘lack-of-delivery-concept’ postulates that HA leads to less carrier mediated uptake of albumin bound substances into hepatocytes and to less glomerular filtration; in contrast, the ‘concept-of-higher-free-fraction’ argues that increased concentrations of non-albumin bound compounds facilitate hepatocellular uptake and enhance glomerular filtration. To address this question, we performed intravital imaging on livers and kidneys of anesthetized mice to quantify the spatio-temporal tissue distribution of the mycotoxin ochratoxin A (OTA) based on its auto-fluorescence in albumin knockout and wild-type mice. HA strongly enhanced the uptake of OTA from the sinusoidal blood into hepatocytes, followed by faster secretion into bile canaliculi. These toxicokinetic changes were associated with increased hepatotoxicity in heterozygous albumin knockout mice for which serum albumin was reduced to a similar extent as in patients with severe hypoalbuminemia. HA also led to a shorter half-life of OTA in renal capillaries, increased glomerular filtration, and to enhanced uptake of OTA into tubular epithelial cells. In conclusion, the results favor the ‘concept-of-higher-free-fraction’ in HA; accordingly, HA causes an increased tissue uptake of compounds with high albumin binding and increased organ toxicity. It should be studied if this concept can be generalized to all compounds with high plasma albumin binding that are substrates of hepatocyte and renal tubular epithelial cell carriers.

Inhibition of cytochrome P450 enhances the nephro- and hepatotoxicity of ochratoxin A

“…For immunohistochemistry, the following primary antibodies were applied: anti-albumin (# ab192603, Abcam; dilution 1:500), anti-CD45 (#550539, BD Bioscience; dilution 1: 400), and anti-FSP1 (#ab197896, Abcam; dilution 1:200). Appropriate secondary antibodies were used (Hassan et al 2022).…”

“…To test if ABT treatment influences OTA transport kinetics, intravital imaging of OTA transport in the livers of mice pre-treated with PBS or ABT was performed using a twophoton microscope (LSM MP7, Zeiss, Germany), as previously described (Hassan 2016;Hassan et al 2022;Remetic et al 2022). Tetramethylrhodamine-ethyl ester (TMRE; #T669, ThermoFisher Scientific) was injected prior to the recording to visualize hepatocyte morphology and lobular zonation (Ghallab et al 2022).…”

“…In a previous study, we observed that hypoalbuminemia enhanced the uptake of OTA into renal tubular epithelial cells, as well as hepatocytes, and led to increased hepatotoxicity 1 3 (Hassan et al 2022). OTA-induced hepatotoxicity showed a pericentral zonation, which is known to occur for substances metabolically activated by cytochrome P450 enzymes that have higher activities in the lobular zone around the central vein (Ghallab et al 2019).…”

“…Investigations into the mechanisms involved in OTAinduced toxicities have included studies on its accumulation in target organs, biotransformation in several species, and its potential role in oxidative stress (Kőszegi and Poór 2016;Mally and Dekant 2009;Ringot et al 2006;Tao et al 2018). Most recently, intravital imaging techniques have been applied to further investigate the subcellular spatio-temporal kinetics of OTA in mice (Ghallab et al 2021a;Hassan et al 2022). Other studies have been performed to unravel the mode of action (MoA) of OTA, for example, to determine if it acts by a DNA-reactive MoA (resulting in mutagenicity) or whether perturbations of other critical cellular processes may explain the nonlinear dose response observed in organ-and site-specific tumor development (Mally 2012;Tozlovanu et al 2012).…”

Site-Directed Spin Labeling EPR Spectroscopy for Determination of Albumin Structural Damage and Hypoalbuminemia in Critical COVID-19

“…Hypoalbuminemia is observed in more than 70% of critical cases of SARS-CoV-2 disease, which is a marker of low survival [ 26 ]. The pharmacokinetics and toxicity of many compounds are influenced by the serum concentrations of this critical protein, with hypoalbuminemia patients having more prolonged clearance to xenobiotics and adverse drug reactions [ 27 ]. The spin-labeling EPR method can be applied as a direct non-invasive approach for monitoring HAS levels in both healthy humans and critical COVID-19 patients.…”