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Abnormal serum transaminases following therapeutic doses of
acetaminophen in the absence of known risk factors.
Kwan D; Bartle WR; Walker SE
Department of Pharmacy' Queen Elizabeth Hospital' Toronto' Ontario'
Dig Dis Sci, 40(9):1951-5 1995 Sep
J.M.' a healthy' 25-year-old male' volunteered for a study involving
warfarin and acetaminophen. acetaminophen 1 g four times a day was
started for 21 days. Liver function tests taken at regular intervals
for the first 12 days were unremarkable. On day 18' however' aspartate
aminotransferase (AST) was 527 IU/liter and alanine aminotransferase
(ALT) was 166 IU/liter. acetaminophen was discontinued and serum
transaminase levels returned to baseline levels two weeks later (AST =
26' ALT = 20). Analysis of J.M.`s urine samples over the first 18 days
showed excretion patterns of glucuronide' sulfate' and glutathione
derived cysteine and mercapturic acid conJugates were similar to the
other subJects in the study. acetaminophen causes hepatotoxicity in
overdose or malnourished or alcoholic patients' none of which applied
to our subJect. Differences in metabolic activation and capacity for
glutathione synthesis can predispose individuals given therapeutic
doses of acetaminophen to adverse effects. Failure to detoxify a highly
reactive metabolite' formed by P-450 metabolism' via glutathione
conJugation is responsible for the development of acute hepatic
necrosis. Accumulation of the toxic metabolite due to depleted
glutathione stores may have occurred with prolonged high dosing in our
subJect and been responsible for his abnormal rise in liver enzymes.

Protective effect of zinc in the hepatotoxicity of bromobenzene and
Szyma]nska JA; Swietlicka EA; Piotrowski JK
Department of Toxicological Chemistry' Medical Academy' L]od]z' Poland.
Toxicology, 66(1):81-91 1991 Feb 11
Mice of the Balb`c strain were administered bromobenzene (BB) or
acetaminophen (AA) i.p.' in single doses of 400 and 300 mg/kg'
respectively. In the blood activity of SGOT and SGPT as well as SDH was
determined. In the liver the level of metallothionein (MT)'
malondialdehyde (MDA) and glutathione (GSH) was measured. The level of
MT as well as GSH (determined as non-protein SH groups) showed a
significant increase following administration of zinc alone. Joint
action of zinc and either BB or AA resulted in a decrease of GSH which
was less pronounced than expected for each of the xenobiotics alone.
The protective effect of zinc reflected in the reduction of the
increase of SGPT and SGOT activity was apparent shortly (4 h) after
administration of AA. A day after inJection of AA alone the activity of
enzymes was lower and the rate of decline followed the sequence SGPT
greater than SGOT greater than SDH. For BB' both the toxic effect and
the protective influence of zinc were apparent 24 h following
administration. At 4 h in a group receiving BB alone no changes of the
indicatory enzymes in blood were noted.

Tissue glutathione levels in mice treated with
Husain S; Ahmed KM
Department of Pharmacology' School of Medicine' University of North
Dakota' Grand Forks 58202.
Pharmacol Biochem Behav, 40(3):513-5 1991 Nov
glutathione (GSH) is widely distributed among living cells and is
involved in many biological functions. It provides the sulfhydryl
groups for conJugation of toxic metabolites of several xenobiotica.
acetaminophen (Tylenol) toxicity is a classical example of this
property. For this purpose' we studied the effects of
delta-9-tetrahydrocannabinol (THC) on tissue levels of GSH in the mice.
Groups of male Swiss Webster mice weighing 25 +/- 5 g were treated with
50 mg/kg' PO THC at 1300 h. Control mice were given equal volume of
sesame oil (5 ml/kg' PO) which was the vehicle for THC. Ninety minutes
following THC administration' mice were sacrificed' their plasma'
brain' heart' liver' kidney and testis were collected. All tissues were
homogenized in 5% TCA/EDTA solution and supernatant solutions of these
homogenates were diluted. In these diluted samples' levels of GSH were
determined by a modified spectrophotometric procedure and the GSH
levels were expressed as micromoles of GSH/g tissue. In this study' THC
caused no effects on GSH levels in brain' heart' testis and plasma.
However' GSH levels in liver and kidney were decreased by 14% and 7%
respectively. Although the decrease in kidney GSH levels were
insignificant' these changes in liver and kidney could be indicative of
a possible metabolic and/or dispositional interaction between THC and
different commonly available drugs such as acetaminophen.

Use of N-acetylcysteine in clinical toxicology.
Flanagan RJ; Meredith TJ
Poisons Unit' Guy`s Hospital' London' U.K.
Am J Med, 91(3C):131S-139S 1991 Sep 30
The maJor use of N-acetylcysteine in clinical toxicology is in the
treatment of acetaminophen (paracetamol) overdosage. The hepatorenal
toxicity of acetaminophen is mediated by a reactive metabolite normally
detoxified by reduced glutathione. If glutathione is depleted' covalent
binding to macromolecules and/or oxidation of thiol enzymes can lead to
cell death. Oral or intravenous N-acetylcysteine or oral D'L-methionine
mitigates acetaminophen-induced hepatorenal damage if given within 10
hours' but becomes less effective thereafter. In vivo' N-acetylcysteine
forms L-cysteine' cystine' L-methionine' glutathione' and mixed
disulfides; L-methionine also forms cysteine' thus giving rise to
glutathione and other products. Oral therapy with N-acetylcysteine or
methionine for acetaminophen poisoning is contraindicated in the
presence of coma or vomiting' or if activated charcoal has been given
by mouth. Nausea' vomiting' and diarrhea may also occur as a result of
oral N-acetylcysteine administration. Anaphylactoid reactions including
angioedema' bronchospasm' flushing' hypotension' nausea/vomiting' rash'
tachycardia' and respiratory distress may occur 15-60 minutes into
N-acetylcysteine infusion (20 hours intravenous regimen) in up to 10%
of patients. Following accidental intravenous overdosage' the adverse
reactions of N-acetylcysteine are similar but more severe; fatalities
have occurred. A reduction in the loading dose of N-acetylcysteine may
reduce the risk of adverse reactions while maintaining efficacy.
Administration of N-acetylcysteine for a longer period might provide
enhanced protection for patients in whom acetaminophen absorption or
elimination is delayed. N-acetylcysteine may also have a role in the
treatment of toxicity from carbon tetrachloride' chloroform'
1'2-dichloropropane' and other compounds. The possible use of
N-acetylcysteine and other agents in the prevention of the
neuropsychiatric sequelae of acute carbon monoxide poisoning is an
important area for future research.

Effect of oleanolic acid on hepatic toxicant-activating and detoxifying
systems in mice.
Liu J; Liu Y; Parkinson A; Klaassen CD
Department of Pharmacology' Toxicology and Therapeutics' University of
Kansas Medical Center' Kansas City' USA.
J Pharmacol Exp Ther, 275(2):768-74 1995 Nov
We have previously shown that oleanolic acid (OA) protects mice against
the hepatotoxicity of carbon tetrachloride' acetaminophen'
bromobenzene' thioacetamide' furosemide' phalloidin' colchicine'
cadmium' D-galactosamine and endotoxin. This study was designed to
examine whether OA modulates hepatic toxicant-activating and
detoxifying systems as a means of protection. Mice were treated with OA
(100 and 200 mumol/kg s.c.) for 3 days' and liver microsomes and
cytosols were prepared 24 hr after the last dose. OA produced a
dose-dependent reduction in liver microsomal cytochrome P450 (P450)
levels (25-37%) and cytochrome b5 (15-21%) content' but had no effect
on NADPH-cytochrome c reductase activity. OA treatment also decreased
several P450 enzyme activities' such as coumarin 7-hydroxylation (45%)'
7-pentoxyresorufin O-dealkylation (35%)' 7-ethoxyresorufin
O-dealkylation (25%) and chlorzoxazone 6-hydroxylation (20%). Treatment
of mice with OA decreased caffeine N3-demethylation (40%)' but had no
effect on caffeine 8-hydroxylation. OA treatment decreased testosterone
6 alpha- and 15 alpha-hydroxylation (40-50%) and androstenedione
formation (35%)' but slightly increased testosterone 1 alpha/beta-' 2
beta- and 6 beta-hydroxylation. Consistent with enzyme activities' OA
decreased the amounts of mouse liver CYP1A and CYP2A enzymes' but had
no appreciable effect on CYP3A enzymes' as determined by immunoblotting
with antibodies against rat P450 enzymes. OA treatment slightly
increased liver glutathione (GSH) content and the activity of GSH
S-transferases toward 1-chloro-2'4-dinitrobenzene' but had no effect on
GSH peroxidase and GSH reductase. The activities of superoxide
dismutase and DT-diaphorase were unaffected by OA treatment. At the
high dose of OA' catalase activity was decreased by 20%.(ABSTRACT

Mechanism of protection of ebselen against paracetamol-induced toxicity
in rat hepatocytes.
Li QJ; Bessems JG; Commandeur JN; Adams B; Vermeulen NP
Department of Pharmacochemistry' VriJe Universiteit Amsterdam' The
Biochem Pharmacol, 48(8):1631-40 1994 Oct 18
The protective effect of ebselen (PZ 51)' an anti-inflammatory agent'
on paracetamol-induced (1 mM) cytotoxicity in hepatocytes freshly
isolated from beta-naphthoflavone-pretreated rats was studied. At a
concentration of 50 microM added simultaneously with paracetamol'
ebselen prevented paracetamol-induced leakage of lactate dehydrogenase
(LDH) almost completely and lipid peroxidation (LPO) and depletion of
glutathione (GSH) substantially. These protective effects were even
more pronounced at 100 microM concentration of ebselen. When added to
the hepatocytes 1 hr before paracetamol' 50 microM of ebselen also
prevented LDH leakage' LPO and GSH depletion. Reverse addition of
paracetamol and ebselen did not result in protection. Simultaneous
incubation of 100 microM ebselen and paracetamol inhibited GSH
conJugation of paracetamol by more than 50%' however' without any
effect on glucuronidation and sulfation of paracetamol. Ebselen was
shown not to react directly with paracetamol nor to inhibit cytochrome
P450 activity measured as 7-ethoxycoumarin O-deethylase (ECD) activity
in the hepatocytes. At mixing' synthetic ebselen selenol and synthetic
N-acetyl-p-benzoquinone imine (NAPQI) were shown to form paracetamol
and ebselen diselenide. No indication was found for the formation of an
ebselen-paracetamol conJugate upon reacting synthetic NAPQI and
synthetic ebselen selenol. Reduction of NAPQI' the reactive metabolite
of paracetamol' by ebselen selenol is discussed in terms of the
mechanism of cytoprotection.

Treatment of advanced malignancies with high-dose acetaminophen and
N-acetylcysteine rescue.
Kobrinsky NL; Hartfield D; Horner H; Maksymiuk A; Minuk GY; White DF;
Feldstein TJ
Department of Pediatrics' University of Saskatchewan' Saskatoon'
Cancer Invest, 14(3):202-10 1996
High-dose acetaminophen (HDAC) produces hepatocellular necrosis and
cytotoxic changes in other tissues that express mixed-function-oxidase
(MFO) activity. N-acetylcysteine (NAC)' administered within 8 hr of
HDAC exposure' replenishes reduced glutathione and prevents these
effects. Numerous cell culture and animal studies have demonstrated
that NAC may differentially protect normal cells compared with
malignant cells from the toxic effects of chemotherapeutic agents and
radiation. It was therefore proposed that HDAC with NAC rescue may be
effective in malignancies that express MFO activity. To test this
hypothesis' a phase I trial of HDAC with NAC rescue was conducted on 19
patients with advanced cancer. HDAC was escalated from 6 to 20 g/m2 PO
using a standard IV NAC rescue regimen. A total of 78 treatments were
administered. Moderate fatigue' anorexia' and weight loss were the main
toxicities observed. Transient grade 3 liver toxicity was noted
following 1 treatment. Alopecia and renal and hematological toxicities
were not observed. Responses after 4 courses administered weekly were
as follows: response in at least 1 site-8 (partial 3' improved 3' mixed
2); stable disease-3; progressive disease-3; inevaluable-5. In
conclusion' HDAC was tolerated with moderate fatigue' anorexia' and
weight loss but few other effects using a standard IV NAC rescue
regimen. A maximum tolerated dose was not reached at 20 g/m2. A 3/19
(15.8%) partial response rate was observed.

[Cytoprotective effect of neurotensin on acetaminophen induced liver
inJury in relation to glutathione system
Li JY; Wang L; Zhang XJ
Department of Physiology' BeiJing Medical University.
Sheng Li Hsueh Pao, 46(2):168-75 1994 Apr
In the present work the cytoprotective effect of neurotensin (NT) on
acetaminophen induced inJury to the liver or cultured hepatocytes of
mouse in relation to glutathione system were investigated. The results
were as follows: Pretreatment with NT significantly reduced the
leakages of transaminases induced by acetaminophen in vivo or in
cultured hepatocytes and partially reversed the decline of DNA
synthesis induced by acetaminophen in cultured hepatocytes. After
administration of acetaminophen to cultured hepatocytes' the contents
of reduced glutathione (GSH) and total glutathione decreased' the
activity of glutathione peroxydase (GSH-Px) decreased' but the contents
of oxidized glutathione (GSSG) showed no change. Pretreatment with NT
before acetaminophen decreased the contents of GSH further but
increased the contents of GSSG and total glutathione and enhanced the
activity of GSH-Px. These results indicated that NT may enhance
synthesis of glutathione and the ability for hepatocytes to scavenge
free radicals by increasing the activity of GSH-Px accompanied by
oxidation of GSH to GSSG.

Oltipraz-induced amelioration of acetaminophen hepatotoxicity in
hamsters. I. Lack of dependence on glutathione.
Davies MH; Schamber GJ; Schnell RC
Department of Pharmaceutical Sciences' North Dakota State University'
Fargo 58105.
Toxicol Appl Pharmacol, 109(1):17-28 1991 Jun 1
These studies were designed to test the hypothesis that oltipraz (OTP)
provided protection against AAP intoxication in a sensitive species'
the hamster; and further' to show that the sparing effect was related
to the marked increase in hepatic reduced glutathione (GSH) levels.
Dose-response and time-course experiments demonstrated that maximal
increases in liver GSH occurred at 48 hr after an oltipraz dose of
approximately 2.0 mmol/kg (po). Accompanying greater GSH levels were
increased glutathione disulfide (GSSG) levels. Decreased indices of the
oxidation state of glutathione and of hepatic pyridine nucleotides
indicated a greater share of glutathione existed as GSH and that
increased reducing equivalents were present' respectively.
Additionally' glutathione disulfide reductase activity was greater in
OTP-treated groups. glutathione S-transferase activities were only
marginally increased. OTP treatment did not elicit observable
hepatotoxicity' whereas AAP (2.6 mmol/kg' ip) resulted in a
reproducible model of liver damage. OTP-treated groups were protected
from AAP-induced toxicity' as shown by decreased plasma appearance of
liver enzymes and unremarkable histopathology. However' the degree of
liver GSH depletion by AAP was fourfold greater in non-OTP treated
groups compared to those which had received the dithiolthione. To test
the importance of increased hepatic GSH' the biosynthesis of
glutathione was interrupted. Buthionine sulfoximine (BSO) treatment
decreased hepatic GSH' the biosynthesis of glutathione was interrupted.
Buthionine sulfoximine (BSO) treatment decreased hepatic GSH content to
50% of control in hamsters which either had or had not received OTP.
The groups receiving BSO and AAP incurred 83% lethality' while no
lethality' unremarkable liver histopathology' and plasma enzyme levels
consistent with control were found in the group receiving OTP' BSO' and
AAP. Treatment with BSO only had no influence on hepatotoxicity
parameters. These results indicate that the increased GSH levels in the
OTP-treated hamster are coincidental to the sparing effect of OTP and
are not central to the protection scheme in AAP-induced hepatotoxicity.

Refining the level for anticipated hepatotoxicity in acetaminophen
Brandwene EL; Williams SR; Tunget-Johnson C; Turchen SG; Manoguerra AS;
Clark RF
UCSD Medical Center 92103-8676' USA.
J Emerg Med, 14(6):691-5 1996 Nov-Dec
Treatment of an acetaminophen overdose with N-acetyl cysteine usually
is based on the position of the 4-h acetaminophen (APAP) level on the
Rumack-Matthew nomogram; however' there is disagreement on the level at
which clinically relevant hepatotoxicity occurs. A retrospective review
of all acute adult formulation APAP exposures reported to our poison
center between 1986 and 1993 was performed and cases corresponding to
the "possible risk or toxicity" range on the nomogram were identified.
Our current poison center protocol for APAP poisoning does not
recommend treatment with N-acetylcysteine (NAC) in low-risk patients if
the 4-h serum APAP level or the extrapolated equivalent falls within
the possible toxicity range on the nomogram. Seventeen cases met the
inclusion criteria for the study and received no NAC; six additional
patients met inclusion criteria but received one or two doses of NAC
before therapy was discontinued. No patients in either group
demonstrated clinical evidence of hepatotoxicity. This pilot study
suggests that patients with no risk factors and APAP levels in the
"possible risk" range may not require NAC therapy.

Effect of colchicine on acetaminophen-induced liver damage.
Muriel P; Quintanar ME; Perez-Alvarez V
Departamento de Farmacologia y Toxicologia' Instituto Politecnico
Nacional' Mexico.
Liver, 13(4):217-21 1993 Aug
The effect of colchicine on liver damage induced by acetaminophen
(APAP) intoxication was studied. Wistar male rats pretreated (72 h)
with 3-methylcholanthrene (3-MC) (20 mg/kg i.p.) were divided into six
groups: animals in group 1 were treated with acetaminophen (APAP) (500
mg/kg p.o.); group 2 consisted of animals that received colchicine (65
micrograms/kg/day p.o.) for 7 days before APAP intoxication; group 3
was treated like group 2' but the dose of colchicine was 300
micrograms/kg/day; animals in groups 4 and 5 received the same doses of
colchicine as groups 2 and 3' respectively' but received the vehicle
instead of APAP; and rats in group 6 (control) received the equivalent
amount of the vehicles. Animals were sacrificed at different times
after APAP administration. Reduced glutathione (GSH)' lipid
peroxidation and glycogen were measured in liver and' gamma-glutamyl
transpeptidase (gamma-GTP)' and glutamic pyruvic transaminase (GPT)
activities were measured in serum. After APAP intoxication' GSH and
glycogen decreased very fast (1 h) and remained low for 6 h. Lipid
peroxidation increased three times over control 4 h after APAP
treatment. Enzyme activities increased at 18 h after intoxication.
Pretreatment with 65 micrograms/kg of colchicine failed to prevent
liver damage induced by APAP. However' when a dose of 300 micrograms/kg
of colchicine was given' levels of lipid peroxidation and serum
gamma-GTP activity remained within the control values' while GPT
activity and glycogen content were only partially attenuated. It was
concluded that colchicine protects against APAP intoxication' probably
through its antioxidant properties' possibly acting as a free radical

cysteine isopropylester protects against paracetamol-induced toxicity.
Butterworth M; Upshall DG; Smith LL; Cohen GM
Toxicology Unit' School of Pharmacy' University of London' U.K.
Biochem Pharmacol, 43(3):483-8 1992 Feb 4
cysteine isopropylester (CIPE)' a novel ester of cysteine' has been
synthesized in order to evaluate its potential as a chemoprotectant.
The increased lipophilicity of the ester relative to cysteine should
facilitate its entry into cells where' following hydrolysis' it should
act as an intracellular source of cysteine or be utilized for the
synthesis of glutathione so protecting the cell against various types
of chemical insult. In this study' we evaluate the ability of CIPE to
protect against paracetamol-induced hepatotoxicity in mice. When
administered to mice' CIPE produced a rapid but transient elevation of
levels of non-protein sulphydryls (NPSH) in liver' lung' kidney and
spleen. The greatest increase in NPSH was seen in the lung' but after
60 min all NPSH values had returned to control levels' demonstrating
the capacity of the mouse to rapidly metabolize both CIPE and cysteine.
In mice pretreated with benzo(a)pyrene' CIPE protected against
paracetamol-induced toxicity as measured by the prevention of
mortality' the fall in hepatic NPSH and the decreased elevation of
serum transaminases. CIPE (1.5 mmol/kg) appeared as effective as
N-acetylcysteine (1.5 mmol/kg). Higher doses of CIPE (3.0 mmol/kg)
alone were toxic to mice induced with benzo(a)pyrene but not to control
or phenobarbitone-induced mice. The mechanism of this increased
toxicity is unclear. CIPE has a short in vivo half life but was capable
of protecting against paracetamol-induced toxicity. The potential of
CIPE and other related cysteine esters to act as chemoprotectants
merits further investigation.

Effects of phenethyl isothiocyanate on acetaminophen metabolism and
hepatotoxicity in mice.
Li Y; Wang EJ; Chen L; Stein AP; Reuhl KR; Yang CS
Laboratory for Cancer Research' Rutgers University' Piscataway' New
Jersey 08855-0789' USA.
Toxicol Appl Pharmacol, 144(2):306-14 1997 Jun
Phenethyl isothiocyanate (PEITC)' a compound derived from cruciferous
and other vegetables' is a potent inhibitor of cytochrome P450 2E1.
This enzyme catalyzes the bioactivation of acetaminophen (APAP) and
many other xenobiotics. The present study investigated the effects of
PEITC on APAP metabolism and associated hepatotoxicity in Swiss-Webster
mice. When PEITC (19-150 micromol/kg) was given to mice
intragastrically 1 hr before or immediately prior to a toxic dose of
APAP' the APAP-induced hepatotoxicity was significantly decreased or
was completely prevented. The extent of toxicity was evaluated by
mortality' serum levels of glutamic-pyruvic transaminase' lactate
dehydrogenase' and liver histopathology. Pretreatment of mice with
ethanol enhanced APAP hepatotoxicity; this enhanced toxicity could also
be prevented by the administration of PEITC. PEITC treatment prevented
the depletion of hepatic glutathione levels caused by oxidized APAP
metabolites. PEITC treatment also significantly decreased the plasma
levels of oxidized APAP metabolites (analyzed as APAP-glutathione'
APAP-cysteine' and APAP-N-acetylcysteine) and reduced the urinary
excretion of APAP-cysteine. In microsomal incubations' PEITC
effectively inhibited the rate of APAP-glutathione formation from APAP
as well as the P450 2E1-dependent N-nitrosodimethylamine demethylase
and the P450 1A2-dependent ethoxyresorufin O-deethylase activities. The
protective action of PEITC against APAP toxicity is attributed to the
blocking of APAP activation through inhibition of P450 enzymes.


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