Calcium channel blocking agents protect against acetaminophen‐induced cytotoxicity in rat hepatocytes

Thibault, Nancy; Peytavin, Gilles; Claude, Jean

doi:10.1002/jbt.2570060310

Cited by 19 publications

(11 citation statements)

References 8 publications

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“…Despite our efforts, we were not able to demonstrate the association between UGT induction and protection against APAP toxicity in the cultured hepatocyte model. Others have reported that treatment of primary rat hepatocytes with APAP at concentrations in the range used in our study (4 mM) results in cytotoxic effects (Milam and Byard, 1985;Thibault et al, 1991). However, we were unable to observe any significant changes in cell morphology or biochemical indices (lactate dehydrogenase and aspartate transaminase) after a 24-h exposure to 4 mM APAP (data not shown).…”

Section: Membranescontrasting

confidence: 61%

Glucuronidation of Acetaminophen Catalyzed by Multiple Rat Phenol UDP-Glucuronosyltransferases

Kessler

Kessler²,

Auyeung³

et al. 2002

Drug Metab Dispos

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ABSTRACT:Gunn rats glucuronidate acetaminophen (APAP) at reduced rates and show increased susceptibility to APAP-induced hepatotoxicity. This defect is presumed to involve UDP-glucuronosyltransferase (UGT) 1A6, which is nonfunctional in Gunn rats, but it is currently unclear whether other 1A family members are also involved. In humans, two 1A isoforms are known to be active (1A6 and 1A9) but 1A6 form has a 25-fold lower apparent K m (2 mM). Rat liver microsomal APAP UGT activity is induced by in vivo treatment with ␤-naphthoflavone or oltipraz, an effect correlating with induction of 1A6 and 1A7. To address a possible role of 1A7 in APAP glucuronidation relative to other 1A forms, cDNAs encoding UGTs 1A1, 1A5, 1A6, 1A7, and 1A8 were expressed in human embryonic kidney cells and the contents of expressed enzyme in prepared membrane fractions determined by quantitative immunoblotting. At 2.5 mM APAP, 1A7 showed the highest specific activity (2.8 nmol/min/nmol 1A7 protein), followed by 1A6 (1.1 nmol/min/nmol), and 1A8 (0.27 nmol/min/nmol). 1A1 and 1A5 were essentially inactive. Kinetic comparisons indicated 1A7 had a similar apparent K m as 1A6 (4.7 versus 3.9 mM, respectively) but a 2.4-fold higher catalytic activity. These data suggest that in rats, 1A7 plays a major role in APAP glucuronidation and contributes to protection against APAP-induced hepatotoxicity. The involvement of other UGTs besides 1A6 is further underscored by the presence of significant residual APAP-glucuronidating activity by Gunn rat hepatocytes, indicating the activity of an unknown UGT2 family member. APAP1 (Tylenol) is a widely used over-the-counter analgesic/ antipyretic drug and model hepatotoxin. Although it is considered safe at normal doses, at higher doses it is associated with a predictable, dose-dependent centrilobular hepatotoxicity (Black, 1984) by a mechanism involving its metabolism to a toxic quinone imine (Cohen and Khairallah, 1997;Bessems and Vermeulen, 2001). APAP undergoes detoxification by competing phase 2 conjugation reactions, glucuronidation and sulfation, which convert APAP to nontoxic conjugates for elimination in bile or urine. The main type of APAP conjugation in most species, including rat and human, is glucuronidation. It has been proposed that individuals who metabolize APAP at slower rates are at higher risk of developing hepatotoxicity, based partly on the known greater susceptibility of animals that are deficient in the glucuronidation of phenols, such as cats (Feloidae) (Court and Greenblatt, 2000;Bessems and Vermeulen, 2001) and the Gunn rat Wells, 1988, 1989).A common assumption has been that the increased susceptibility of cats and Gunn rats to APAP toxicity is due to inactive UGT1A6, a major liver-expressed phenol UGT. The wild-type 1A6 2 enzyme from rat and human is effective in APAP catalysis (Bock et al., 1993), and in rats, 1A6 is induced by 3-methylcholanthrene (Munzel et al., 1994;Bock et al., 1999), which results in increased APAP glucuronidation (Gregus et al., 1990; Bock et al., 1993). In ca...

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Section: Membranescontrasting

confidence: 61%

Glucuronidation of Acetaminophen Catalyzed by Multiple Rat Phenol UDP-Glucuronosyltransferases

Kessler

Kessler²,

Auyeung³

et al. 2002

Drug Metab Dispos

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“…Calcium contents in liver cells are liable to be increased during the process of experimental liver damage (Moore et al, 1985;Tusokos-Kuhn, 1989) and calcium channel blocking drugs, i.e. nifedipine and verapamil were found to inhibit the development of hepatic damage induced by different hepatotoxins including paracetamol and CCl 4 (Landon et al, 1986;Thibault et al, 1991). Interestingly, CSE was found to exhibit the calcium channel blocking activity in this study and thus, hepatoprotective activity of CSE against paracetamol and CCl 4 -induced damage reported in this study may be partly attributed to its calcium channel blocking activity.…”

Section: Resultsmentioning

confidence: 98%

Studies on the antihypertensive, antispasmodic, bronchodilator and hepatoprotective activities of the Carum copticum seed extract

Gilani

Jabeen

Ghayur

et al. 2005

Journal of Ethnopharmacology

154

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“…In hepatocytes, increases in [Ca 2ϩ ] i are associated with cytotoxicity (9) arising from diverse agents such as carbon tetrachloride (10,11), paracetamol (12)(13)(14), extracellular ATP (15- 19), and hydrophobic bile acids (20). Elevated [Ca 2ϩ ] i also injures hepatocytes in several pathophysiological liver conditions, including ischemia-reperfusion injury (6,21), endotoxaemia (22), and hemorrhagic shock (23).…”

Section: Elevations In Intracellular Camentioning

confidence: 99%

Atrial Natriuretic Peptide Attenuates Elevations in Ca2+ and Protects Hepatocytes by Stimulating Net Plasma Membrane Ca2+ Efflux

Green

Stratton

Squires

et al. 2007

Journal of Biological Chemistry

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Elevations in intracellular Ca2؉ concentration and calpain activity are common early events in cellular injury, including that of hepatocytes. Atrial natriuretic peptide is a circulating hormone that has been shown to be hepatoprotective. The aim of this study was to examine the effects of atrial natriuretic peptide on potentially harmful elevations in cytosolic free Ca 2؉ (24) that plays a key role in initiation of cellular injury and subsequent necrosis or apoptosis (6,(25)(26)(27)(28)(29)(30). In hepatocytes, calpain promotes hepatocyte plasma membrane blebbing (31), induces the mitochondrial permeability transition in hepatocyte necrosis (32), and contributes to hepatocyte necrosis in anoxia (33). Calpain has been implicated in hepatotoxicity in ischemia-reperfusion injury (34, 35), hemorrhagic shock (36), and bile acid toxicity (20).In the search for cytoprotective agents and therapeutic interventions, those which suppress injurious [Ca 2ϩ ] i rises are considered highly promising (2-6, 30). Natriuretic peptides attenuate elevations in cytosolic free Ca 2ϩ concentration ([Ca 2ϩ ] c ) in many cell types (37-50), including rat hepatocytes (51). Atrial natriuretic peptide (ANP) 3 is a circulating hormone released mainly by atrial myocytes (52) in response to stress conditions such as volume expansion or cardiac hypoxia. In addition to its hypotensive, vasodilatory, and natriuretic effects in the cardiovascular and renal systems (53), increasing evidence supports a more widespread role for ANP in several other organs (54), including the liver. ANP elevates cGMP in rat hepatocytes (51,(55)(56) through the guanylyl cyclase A receptor (57), and is cytoprotective in both isolated hepatocytes (51,55,58) and perfused liver (57, 59 -62). An early preliminary study showed that ANP attenuated both oxidant-induced cell injury and the accompanying [Ca 2ϩ ] i rise (51), suggesting that the hepatoprotective effects of ANP may be mediated by mechanisms involved in Ca 2ϩ homeostasis (51, 55, 57). We have since examined the effects of ANP on physiological alterations in [Ca 2ϩ ] c ; we showed that ANP, through protein kinase G (PKG), attenuates [Ca 2ϩ ] c oscillations, dramatically increases the basal rate of plasma membrane Ca 2ϩ efflux and modestly inhibits basal Ca 2ϩ influx in rat hepatocytes (56).

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Calcium channel blocking agents protect against acetaminophen‐induced cytotoxicity in rat hepatocytes

Cited by 19 publications

References 8 publications

Glucuronidation of Acetaminophen Catalyzed by Multiple Rat Phenol UDP-Glucuronosyltransferases

Glucuronidation of Acetaminophen Catalyzed by Multiple Rat Phenol UDP-Glucuronosyltransferases

Studies on the antihypertensive, antispasmodic, bronchodilator and hepatoprotective activities of the Carum copticum seed extract

Atrial Natriuretic Peptide Attenuates Elevations in Ca2+ and Protects Hepatocytes by Stimulating Net Plasma Membrane Ca2+ Efflux

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