Oltipraz-induced amelioration of acetaminophen hepatotoxicity in hamsters

Davies, Meirion; Schamber, George; Schnell, R.

doi:10.1016/0041-008x(91)90187-j

Cited by 23 publications

(8 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly, we have also reported that CFB does not aå ect the capacity of the liver to conjugate APAP with glucuronic acid or sulphate, which are the main detoxi® cation pathways for APAP (Manautou et al 1996). In the past, hepatoprotective treatment regimens that enhance hepatic glucuronide conjugation prevent the toxic eå ects of APAP by increasing substantially the formation and disposition of APAP-glucuronide conjugate (Madhu and Klaassen 1991, Davies and Schnell 1991, Liu et al 1993. The lack of changes in biliary output of APAP-GLU due to CFB pretreatment in the current studies, along with previous observations from urinary metabolites studies (Manautou et al 1996), further supports the absence of changes in hepatic APAP glucuronidation.…”

Section: Discussionmentioning

confidence: 84%

Effects of clofibrate and indocyanine green on the hepatobiliary disposition of acetaminophen and its metabolites in male CD-1 mice

Chen¹,

Hennig

McCann

et al. 2000

Xenobiotica

View full text Add to dashboard Cite

1. The effects of clofibrate (CFB) and indocyanine green (ICG) on the biliary excretion of acetaminophen (APAP) and its metabolites were investigated. 2. Male CD-1 mice were pretreated with 500 mg CFB/kg, i.p. for 10 days. Controls received corn oil vehicle only. After overnight fasting, common bile duct-cannulated mice were challenged with a non-toxic dose of APAP (1 mmol/kg, i.v.). 3. CFB pretreatment did not affect bile flow rate, nor did it affect the cumulative biliary excretion of APAP and its conjugated metabolites. 4. Additional CFB or corn oil pretreated mice were given 30 mumol indocyanine green (ICG)/kg, i.v., immediately before APAP dosing. ICG is a non-metabolizable organic anion that is completely excreted into the bile through a canalicular transport process for organic anions. 5. ICG significantly decreased the bile flow rate and biliary concentration of APAP-glutathione, APAP-glucuronide and APAP-mercapturate within the first hour after dosing without affecting the biliary concentration of APAP. 6. The results indicate that CFB pretreatment does not affect the total amount of APAP and its metabolites excreted in bile. They also suggest that the biliary excretion of several conjugated metabolites of APAP share the same excretory pathway with the organic anion ICG.

show abstract

Section: Discussionmentioning

confidence: 84%

Effects of clofibrate and indocyanine green on the hepatobiliary disposition of acetaminophen and its metabolites in male CD-1 mice

Chen¹,

Hennig

McCann

et al. 2000

Xenobiotica

View full text Add to dashboard Cite

show abstract

“…Groups of four hamsters were treated with E 2 . For time-course studies, the animals were intraperitoneally injected with 8 μmol of E 2 dissolved in 300 μL of trioctanoin/DMSO (9:1, v/v) per 100 g of body weight and maintained for 1, 2, or 4 h. For studies with BSO, the animals were subcutaneously injected with 0.6 mmol of BSO in 2 mL of 0.9% saline (per 100 g of body weight) ( , ) 2.5 h before injection of 8 μmol of E 2 , dissolved in 300 μL of trioctanoin/DMSO (9:1, per 100 g of body weight) and maintained 2 h after treatment with E 2 . Control hamsters were left untreated or treated only with the vehicle and maintained for 2 h. The liver and kidney tissues were collected and stored at −80 °C until use.…”

Section: Methodsmentioning

confidence: 99%

“…To confirm that the oxidative pathway of CE to CE-Q is more pronounced in the kidney, a target tissue for estrogen carcinogenesis, than in the refractory liver, hamsters were treated with BSO to deplete GSH levels (29,30). The dose and time of pretreatment with BSO were selected based on similar studies of GSH depletion conducted in rats (30) and hamsters (29). In rats, the levels of GSH were 70-80% in the kidney and liver (30).…”

Section: Time-response In E 2 -Treated Hamstersmentioning

confidence: 99%

“…The first study involved treatment of hamsters with exogenous E 2 . The second one examined the effects of E 2 and lowered GSH levels, achieved by treatment of the hamsters with l -buthionine( S , R )sulfoximine (BSO), a specific inhibitor of γ-glutamylcysteine synthetase that is involved in the GSH biosynthesis pathway ( , ). These studies were conducted in the kidney, which is a good model for estrogen-induced carcinogenesis ( , ), and the liver, a nontarget tissue.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Imbalance of Estrogen Homeostasis in Kidney and Liver of Hamsters Treated with Estradiol: Implications for Estrogen-Induced Initiation of Renal Tumors

Cavalieri

Kumar

Todorovic

et al. 2001

Chem. Res. Toxicol.

View full text Add to dashboard Cite

Reaction of endogenous catechol estrogen quinones (CE-Q) with DNA may initiate cancer by generation of oncogenic mutations. Treatment of male Syrian golden hamsters with estrogens or 4-catechol estrogens (4-CE), but not 2-CE, induces kidney, but not liver, tumors. The hamster provides an excellent model for studying activation and deactivation (protection) of estrogen metabolites in relation to formation of CE-Q. Several factors can unbalance estrogen homeostasis, thereby increasing the oxidative pathway leading to the carcinogenic CE-3,4-Q. Hamsters were injected with 8 micromol of estradiol (E(2)), and liver and kidney extracts were analyzed for 31 estrogen metabolites, conjugates, and depurinating DNA adducts by HPLC with electrochemical detection. Neither liver nor kidney contained 4-methoxyCE, presumably due to the known inhibition of catechol-O-methyltransferase by 2-CE. More O-methylation of 2-CE was observed in the liver and more formation of CE-Q in the kidney. These results suggest less protective methylation of 2-CE and more pronounced oxidation of CE to CE-Q in the kidney. To investigate this further, hamsters were pretreated with L-buthionine(S,R)-sulfoximine to deplete glutathione levels and then treated with E(2). Compared to the liver, a very low level of CE and methoxyCE was observed in the kidney, suggesting little protective reductase activity. Most importantly, reaction of CE-3,4-Q with DNA to form the depurinating 4-hydroxyE(2)(E(1))-1-N7Gua adducts was detected in the kidney, but not in the liver. Therefore, tumor initiation in the kidney appears to arise from relatively poor methylation of 2-CE and poor reductase activity in the kidney, resulting in high levels of CE-Q. Thus, formation of depurinating DNA adducts by CE-3,4-Q may be the first critical event in the initiation of estrogen-induced kidney tumors.

show abstract

“…For example, hepatotoxicity was decreased by inhibiting or increased by inducing CYP450 (Mitchell et al, 1973a), and administration of Nacetyl-L-cysteine, which replenishes hepatic glutathione (GSH), has been used to ameliorate APAP toxicity (Prescott and Critchley, 1983;Mitchell et al, 1973b). In addition, increasing APAP's detoxification through conjugation with glucuronic acid by treatment with butylated hydroxyanisole, pregnenolone-16a-carbonitrile, oltipraz, or oleanolic acid protects against APAP hepatotoxicity (Hazelton et al, 1896;Madhu and Klaassen, 1991;Davies et al, 1991;Liu et al, 1993).…”

mentioning

confidence: 99%

Protection against Acetaminophen Hepatotoxicity by a Single Dose of Clofibrate: Effects on Selective Protein Arylation and Glutathione Depletion

et al. 1996

View full text Add to dashboard Cite

Previous reports demonstrated that repeated administration of peroxisome proliferators protects against acetaminophen (APAP) hepatotoxicity in mice. This protection was associated with a decrease in APAP's selective protein arylation and glutathione depletion. This study was conducted to determine if a single dose of clofibrate (CFB), rather than repeated doses, would similarly prevent APAP toxicity. CD-I male mice received a single dose of 500 mg CFB/kg and controls were given corn oil 24 hr prior to APAP challenge. After an 18-hr fast, mice were challenged with 800 mg APAP/kg (in 50% propylene glycol) and killed at 4 or 12 hr. Other mice similarly pretreated were killed without APAP challenge. The results showed that pretreatment with a single CFB dose significantly decreased APAP-induced hepatotoxicity. At 12 hr after APAP plasma sorbitol dehydrogenase activity and the severity of hepatocellular necrosis were decreased in CFB pretreated mice. Surprisingly, no differences in hepatic nonprotein sulfhydryl (NPSH) depletion or selective arylation of target proteins in cytosol were observed at 4 hr after APAP challenge. Neither did a single dose of CFB significantly alter hepatic NPSH content prior to APAP challenge. These results indicate that protection against APAP hepatotoxicity by CFB does not require repeated administration, and the absence of significant alterations in APAP's selective protein arylation or glutathione depletion suggests that the protection against APAP hepatotoxicity after a single treatment with CFB may differ mechanistically from the protection observed after repeated CFB dOSing.

show abstract

Oltipraz-induced amelioration of acetaminophen hepatotoxicity in hamsters

Cited by 23 publications

References 24 publications

Effects of clofibrate and indocyanine green on the hepatobiliary disposition of acetaminophen and its metabolites in male CD-1 mice

Effects of clofibrate and indocyanine green on the hepatobiliary disposition of acetaminophen and its metabolites in male CD-1 mice

Imbalance of Estrogen Homeostasis in Kidney and Liver of Hamsters Treated with Estradiol: Implications for Estrogen-Induced Initiation of Renal Tumors

Protection against Acetaminophen Hepatotoxicity by a Single Dose of Clofibrate: Effects on Selective Protein Arylation and Glutathione Depletion

Contact Info

Product

Resources

About