When used in overdoses, acetaminophen (APAP) is a common cause of morbidity and mortality in humans. At present, N-acetylcysteine (NAC) is the antidote of choice for acetaminophen overdoses. Prompt administration of NAC can prevent the deleterious actions of APAP in the liver. In view of the similarities in antioxidant effects demonstrated by NAC, hypotaurine (HYTAU) and taurine (TAU) in this and other our laboratories, the present study was undertaken to compare these compounds for the ability to attenuate plasma and liver biochemical changes associated with a toxic dose of APAP. For this purpose, fasted male Sprague-Dawley rats, 225-250 g in weight, were intraperitoneally treated with APAP (800 mg/kg), NAC, HYTAU or TAU (2.4 mM/kg) followed 30 min later by APAP, or 50% PEG 400 (the vehicle for APAP). At 6 hr after APAP administration, all animals were sacrificed by decapitation and their blood and livers collected. The plasma fractions were analyzed for indices of liver damage (alanine transaminase, aspartate transaminase, lactate dehydrogenase), levels of malondialdehyde (MDA), reduced (GSH) and oxidized (GSSG) glutathione, and activities of glutathione reductase (GR), glutathione S-transferase (GST) and γ-glutamylcisteinyl synthetase (GCS). Suitable liver homogenates were analyzed for the same biochemical parameters as the plasma but indices of liver damage. By itself, APAP increased MDA formation and had a significant lowering influence on the levels of GSH and GSSG, the GSH/GSSH ratio, and the activities of GR, GST and GCS both in the plasma and liver. In addition, APAP promoted the leakage of transaminases and lactate dehydrogenase from the liver into the plasma. Without exceptions, a pretreatment with a sulfur-containing compound led to a significant attenuation of the liver injury and the biochemical changes induced by APAP. Within a narrow range of potency differences, HYTAU appeared to be the most protective and TAU the least. The present results suggest that, irrespective of the differences in structural features and in vitro antioxidant properties that may exist among NAC, TAU and HYTAU, these compounds demonstrate equivalent patterns of protection and, to a certain extent, equipotent protective actions against the toxic actions of APAP in the liver when tested in equimolar doses and under the same conditions in an animal model.

The present study was carried out to ascertain the impact of replacing the sulfonate group of TAU with thiosulfonate, as present in thiotaurine (TTAU), on the protective actions of TAU against hepatocellular damage and biochemical alterations related to oxidative stress and glutathione redox cycling, synthesis, and utilization caused by a high dose of acetaminophen (APAP). To this end, male Sprague-Dawley rats, 225-250 g, were intraperitoneally treated with a 2.4 mmol/kg dose of TAU (or TTAU), followed 30 min later by 800 mg/kg of APAP. A reference group received 2.4 mmol/kg of N-acetylcysteine (NAC) prior to APAP. Naive rats served as controls. The animals were sacrificed 6 h after receiving APAP and their blood and livers were collected. Plasma and liver homogenates were analyzed for indices of cell damage (plasma transaminases, plasma lactate dehydrogenase), -oxidative stress (malondialdehyde = MDA, reduced glutathione = GSH, glutathione disulfide = GSSG, catalase, glutathione peroxidase, superoxide dismutase), glutathione cycling (glutathione reductase), utilization (glutathione S-transferase), and synthesis (γ-glutamylcysteine synthetase) activities. APAP increased MDA formation and lowered the GSH/GSSG ratio and all enzyme activities, especially those of antioxidant enzymes. In general, TTAU was equipotent with NAC and more potent than TAU in protecting the liver. Taken into account the results of a previous study comparing the actions of TAU and hypotaurine (HTAU), the sulfinate analog of TAU, it appears that the sulfinate and thiosulfonate analogs are somewhat more effective than the parent sulfonate TAU in counteracting APAP-induced hepatic alterations in the liver and plasma.

A simple reversed-phase HPLC method for measuring hepatic levels of acetaminophen- (APAP-) protein adduct following an overdose of APAP was developed. An aliquot of liver homogenate in phosphate-buffered saline pH 7.4 (PBS) was placed on a Nanosep centrifugal device, which was centrifuged to obtain a protein residue. This residue was incubated with a solution of p-aminobenzoic acid (PABA), the internal standard, and bacterial protease in PBS, transferred to a Nanosep centrifugal device, and centrifuged. A 100 μL portion of the filtrate was analyzed on a YMC-Pack ODS-AMQ C18 column, using 100 mM potassium dihydrogen phosphate-methanol-acetic acid (100 : 0.6 : 0.1) as the mobile phase, a flow rate of 1 mL/min, and photometric detection at 254 nm. PABA and APAP-cystein-S-yl (APAP-Cys) eluted at ~14.7 min and 22.7 min, respectively. Method linearity, based on on-column concentrations of APAP-Cys, was observed over the range 0.078–40 μg. Recoveries of APAP-Cys from spiked blank liver homogenates ranged from ~83% to 91%. Limits of detection and of quantification of APAP-Cys, based on column concentrations, were 0.06 μg and 0.14 μg, respectively. RSD values for interday and intraday analyses of a blank liver homogenate spiked with APAP-Cyst at three levels were, in all cases, ≤1.0% and <1.5%, respectively. The proposed method was found appropriate for comparing the antidotal properties of N-acetylcysteine and taurine in a rat model of APAP poisoning.

Taking into account the ability of vitamin B6 vitamers (i.e., pyridoxal, pyridoxine, pyridoxamine) to stimulate adrenomedullary catecholamine outflow and biochemical and cardiovascular changes consistent with adrenoceptor stimulation, this study was undertaken in mice to verify the possibility that pyridoxal (PL), the most potent of the B6 vitamers, could enter into an adverse vitamin-drug interaction when coadministered with a cardioactive drug, and that compounds like taurine (TAU) and labetalol (LAB) could be protective. To this end, mice were treated with PL (200 mg/kg) and isoproterenol (ISO 200 mg/kg), with and without a pretreatment with TAU (300 mg/kg), LAB (30 mg/kg), or TAU plus LAB, and monitored for heart rate, electrocardiographic (ECG) and myocardial electrolyte changes. PL plus ISO lowered the LD50 of ISO and magnified the changes in heart rate, ECG and myocardial electrolytes seen with ISO alone. Pretreating rats with TAU or TAU plus LAB attenuated the cardiovascular changes induced by PL plus ISO to a greater extent than LAB alone. The attenuating actions of TAU and LAB probably reflect independent and complementary mechanisms of action.