Comparative Evaluation of the Effects of Taurine and Thiotaurine on Alterations of the Cellular Redox Status and Activities of Antioxidant and Glutathione-Related Enzymes by Acetaminophen in the Rat - Advances in Experimental Medicine and Biology - page 186

Abbreviations

APAP Acetaminophen

TAU Taurine

TTAU Thiotaurine

N A C N -acetylcysteine

ALT Alanine transaminase

AST Aspartate transaminase

LDH Lactate dehydrogenase

MDA Malondialdehyde

GSH Reduced glutathione

GSSG Glutathione disul fi de

CAT Catalase

SOD Superoxide dismutase

GPx Glutathione peroxidase

GS γ -Glutamylcysteine synthetase

GR Glutathione reductase

GST Glutathione S-transferase

20.1 Introduction

Acetaminophen ( N -acetyl- p -aminophenol, APAP) is a synthetic centrally acting
compound widely used for its analgesic and antipyretic effects in infants, children,
and adults. At therapeutic doses this over-the-counter medication is well tolerated,
but in overdoses it is one of the most common causes of both intentional and unin-
tentional poisoning and toxicity, often culminating in hepatic failure and even death
(Chung et al. 2009 ; Lee 2007 ) .
The toxicity of APAP is closely linked to its hepatic metabolism, which may
involve the depletion of protein and glutathione thiol groups, the elevation of the
cytoplasmic Ca 2+ (Moore et al. 1985 ), and the development of oxidative/nitrosative
stress (Jaeschke et al. 2003 ; van de Straat et al. 1987 ) .
After the ingestion of a standard dose of APAP, up to 90% of this phenolic com-
pound enters into hepatic conjugation at the meta -position to yield innocuous
glucuronide (~55%) and sulfate (35%) conjugates, with only a small fraction (about
5-10%) undergoing metabolism to the toxic electrophile N -acetyl- para -
benzoquinoimine (NAPQI) by hepatic cytochrome P450 isoforms, mainly CYP
2E1, CYP 1A2, and CYP 3A2 (Bessems and Vermeulen 2001 ; Patten et al. 1993 ;
Smilkstein et al. 1988 ). At low doses of APAP, NAPQI is conjugated with glutathi-
one and subsequently excreted in the urine as the mercapturic acid and cysteine
derivatives (Patten et al. 1993 ). At high doses of APAP, however, the normal conju-
gating pathways for this compound become rapidly saturated and a greater propor-
tion of the drug is available for conversion to NAPQI, which then depletes the