Hepatotoxin-induced hypertyrosinemia and its toxicological significance

Abstract

A (1)H Nuclear Magnetic Resonance (NMR) spectroscopic investigation of the effects of single doses of four model hepatotoxins on male Sprague-Dawley rats showed that hypertyrosinemia was induced by three of the treatments (ethionine 300 mg/kg, galactosamine hydrochloride 800 mg/kg and isoniazid 400 mg/kg) but not by the fourth (thioacetamide 200 mg/kg). Concomitant histopathological and clinical chemistry analyses showed that hypertyrosinemia could occur with or without substantial hepatic damage and that substantial hepatic damage could occur without hypertyrosinemia. However, in the rats dosed with galactosamine hydrochloride, which showed highly variable amounts of liver damage at ca. 24 h after dosing, a clear relationship was found between the degree of hypertyrosinemia and the extent of the hepatic necrosis induced. In line with the cause of clinically observed Type II Tyrosinemia, we consider that the critical event in the onset of hepatotoxin-induced hypertyrosinemia is likely to be a reduction in hepatic tyrosine aminotransferase (TAT) activity. We discuss mechanisms by which TAT activity could be lost with special consideration given to pyridoxal 5'-phosphate (P5P) depletion and to the inhibition of protein synthesis. This analysis may have implications for the interpretation of clinical measures of liver status such as Fischer's ratio and the branched-chain tyrosine ratio (BTR).

Dexamethasone Pretreatment Alleviates Isoniazid/Lipopolysaccharide Hepatotoxicity: Inhibition of Inflammatory and Oxidative Stress

“…DEX was also given as a single dose at day 14, 1 h prior LPS administration. These selected concentrations were in accordance with previous research on INH/LPS combinations (Clayton et al, 2007; Metushi et al, 2012; Su et al, 2014; Hassan et al, 2016) and DEX (Dandona et al, 1999; Eum et al, 2003; Cui et al, 2015). Rats were sacrificed after INH last dose; blood was collected, allowed to clot at room temperature and centrifuged for serum.…”

Site and Strain-Specific Variation in Gut Microbiota Profiles and Metabolism in Experimental Mice

“…Such variation may for example, significantly influence drug metabolism within apparently identical mouse strains [5]. Specific metabonomic studies have shown that individual, pre-dose urinary metabolic phenotypes (which are strongly influenced by the microbiota [39] can be used to predict the metabolic fate and toxicity of drugs and other xenobiotics in animals [8] and the urinary metabolic phenotype of human volunteers was recently found to predict the metabolic fate of acetaminophen (paracetamol) based on the quantity of urinary p-cresol, a product of gut microbial metabolism [40], [41].…”

Application of GC/MS-based metabonomic profiling in studying the lipid-regulating effects of Ginkgo biloba extract on diet-induced hyperlipidemia in rats

“…As it targets a quantitative measurement of the global and dynamic metabolic responses of living systems to biological stimuli and genetic modification [14,15] , metabonomics provides an integrated view of biochemistry in complex organisms, as well as global outcomes of system biology and environmental and lifestyle factors [15] . The approach has been applied widely and successfully to disease state diagnosis [16][17][18][19] , pharmaceutical research and development [20] , drug toxicity evaluation [14,21] , therapeutic monitoring and other related topics [22] . As such, metabonomics may monitor metabolic responses in complex systems when TCM is applied.…”