Immunohistochemical Localization of Acetaminophen in Target Tissues of the CD-1 Mouse: Correspondence of Covalent Binding with Toxicity

Hart, Susan; Cartun, Richard W.; Wyand, D. S.; Khairallah, Edward A.; Cohen, Steven D.

doi:10.1006/faat.1995.1029

Cited by 81 publications

(52 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It (8). Still others (e.g., 3,3'-iminodipropionitrile, 3-methylindole, 2,6-dichlorobenzonitrile, nitrosamines, bromobenzene, acetaminophen) cause olfactory mucosal damage following iv or ip injection (2,4,10,12,25). While the role of blood flow in regional deposition of such compounds as the mechanism underlying the site specificity of lesion development is currently under investigation (18) (27,30 (20,21 ).…”

Section: Discussionmentioning

confidence: 99%

Olfactory Toxicity of Methimazole: Dose-Response and Structure-Activity Studies and Characterization of Flavin-Containing Monooxygenase Activity in the Long-Evans Rat Olfactory Mucosa

et al. 1995

View full text Add to dashboard Cite

Methimazole is a compound administered to humans for the treatment of hyperthyroidism and is used experimentally as a model substrate for the flavin-containing monooxygenase (FMO) system. Previous results from this laboratory demonstrated that methimazole is an olfactory system toxicant, causing nearly complete destruction of the olfactory epithelium in the male Long-Evans rat following a single ip dose of 300 mg/kg.The present studies were undertaken to determine the dose-response relationship for methimazole-induced olfactory mucosal damage and to determine whether or not similar damage occurs as a result of oral administration, mimicking the relevant route of human exposure. We also investigated the mechanism of olfactory toxicity of methimazole by means of a structure-activity study and began the characterization of the form(s) of FMO present in the olfactory mucosa of the male Long-Evans rat. Dose-response analysis demonstrated that methimazole causes olfactory mucosal damage at doses of 25 mg/kg ip and greater. The results of gavage studies showed that a single oral dose of 50 mg/kg also caused olfactory mucosal damage. Two structurally related compounds, methylimidazole and methylpyrrole, were not olfactory toxicants, suggesting that a reactive intermediate generated in the course of metabolizing methimazole to an S-oxide is the olfactory toxic species. Microsomal incubation studies revealed the presence ofmethimazole S-oxidation activity in olfactory mucosal microsomes at levels comparable to those in liver. An anti-mouse liver FMO antibody reacted on Western blots with olfactory mucosal microsomes. These findings demonstrate a doseresponse for the olfactory toxicity of methimazole and suggest that characterization of human olfactory mucosal FMO activity may be necessary to assess the potential for human risk associated with therapeutic exposure to methimazole.

show abstract

Section: Discussionmentioning

confidence: 99%

Olfactory Toxicity of Methimazole: Dose-Response and Structure-Activity Studies and Characterization of Flavin-Containing Monooxygenase Activity in the Long-Evans Rat Olfactory Mucosa

et al. 1995

View full text Add to dashboard Cite

show abstract

“…In the kidney, several enzymes, including P450, prostaglandin endoperoxide synthase, and N-deacetylase, are believed to be involved in acetaminophen toxicity in the several species that have been examined (Larsson et al, 1985;Newton et al, 1985;Emeigh Hart et al, 1994). An immunohistochemical analysis demonstrated that covalent binding of acetaminophen and the associated tissue damage colocalize with CYP2E1 expression sites in the liver and various extrahepatic tissues (including lung, kidney, and OE) in CD-1 mice (Emeigh Hart et al, 1995), suggesting that toxicity in these tissues was associated with metabolic activation of acetaminophen by local P450s. It has also been postulated that 4-aminophenol, formed through an NADPH-independent deacetylation of acetaminophen, is important for the neph -TABLE 3 Capacity for acetaminophen metabolic activation was not changed in OE, lung, and kidney of the Null mice Kidney and lung microsomes and OE S9 fractions of 3-to 4-month-old male mice were analyzed for the rates of formation of GS-AP from acetaminophen (0.5 mM), as described under Materials and Methods.…”

Section: Mechanisms Of Extrahepatic Acetaminophen Toxicity 627mentioning

confidence: 99%

In Vivo Mechanisms of Tissue-Selective Drug Toxicity: Effects of Liver-Specific Knockout of the NADPH-Cytochrome P450 Reductase Gene on Acetaminophen Toxicity in Kidney, Lung, and Nasal Mucosa

et al. 2004

View full text Add to dashboard Cite

Acetaminophen overdose causes toxicity in liver and extrahepatic tissues. Although it is well established that cytochrome P450 enzymes play a critical role in the metabolic activation of acetaminophen, it is not yet clear whether acetaminophen toxicity in extrahepatic tissues is a consequence of hepatic biotransformation. The aim of this study was to determine whether extrahepatic acetaminophen toxicity is altered in a mouse model that has liver-specific deletion of the NADPH-cytochrome P450 reductase (Cpr) gene. Liver-specific Cpr-null (Null) mice were resistant to acetaminophen hepatotoxicity, and they showed faster acetaminophen clearance than did wildtype mice at a toxic acetaminophen dose (400 mg/kg i.p.). However, when circulating acetaminophen levels were made equivalent in the two strains, the severity of extrahepatic acetaminophen toxicity was decreased in the Null relative to that in the wild-type mice in the lung, kidney, and lateral nasal glands, although not in the nasal olfactory and respiratory mucosa. In the lung and liver, the decreased acetaminophen toxicity was accompanied by substantial decreases in the formation of acetaminophen-protein adducts in the Null mice; adducts were not detected in other tissues examined. These results indicate that acetaminophen toxicity in the nasal mucosa is not dependent on hepatic microsomal P450-catalyzed metabolic activation and that acetaminophen toxicity in the lung, kidney, and lateral nasal glands is at least partly caused by liver-derived acetaminophen metabolites.

show abstract

“…Phosphorylase kinase re-DISCUSSION mains capable of phosphorylase a activation via the cAMP pathway, and this response is insensitive to inhibition by Covalent modification of DNA as a result of APAP toxicity occurs in vitro. 27 The relevance of DNA repair mechanisms EGTA. In summary, APAP-induced phosphorylase a activation can be blocked by Ca 2/ chelation with minimal effects to APAP hepatotoxicity has been shown in mouse studies in vivo.…”

mentioning

confidence: 99%

Calcium-dependent DNA damage and adenosine 3′,5′-cyclic monophosphate- independent glycogen phosphorylase activation in an in vitro model of acetaminophen-induced liver injury

Salas

Corcoran

1997

Hepatology

View full text Add to dashboard Cite

APAP-induced necrotic death. Results with these in Acetaminophen (N-acetyl-p-aminophenol [APAP]) hepa-vitro models of liver injury are interpreted as supporting totoxicity is a process characterized by Ca 2/ deregulathe hypothesis that increased Ca 2/ availability plays a tion. Cellular functions utilizing Ca 2/ as a second mesmajor role in the progression of APAP-dependent cellusenger molecule affect both cytosolic and nuclear signal lar necrosis, and that the nucleus is a critical target for transduction. Many studies have independently shown APAP hepatotoxicity. (HEPATOLOGY 1997;25:1432-1438.) Ca 2/ -related effects on target molecules in response to toxic doses of APAP; however, the primary Ca 2/ target resulting in liver necrosis has not been determined. WeAcute exposure to toxic doses of acetaminophen (N-acetylhypothesize that Ca 2/ -dependent DNA damage is a critip-aminophenol [APAP]) induces cellular responses driven by cal event in liver necrosis caused by alkylating hepatodisruption of Ca 2/ homeostasis and is strongly correlated to toxins. In this study, Ca 2/ -dependent endonuclease ac-DNA damage in the liver. 1-3 At lethal doses, organ failure tivity was determined from DNA single-strand lesions ensues via mechanisms that produce cell death by necrosis measured by fluorometric analysis of DNA unwinding.and possibly apoptosis. Strategies to treat individuals after The status of cytosolic Ca 2/ was determined by measurtoxic exposure are limited by our understanding of the relaing Ca 2/ -dependent activation of glycogen phosphoryltive contributions of events that produce irreversible damage ase a. Primary cultures of mouse hepatocytes exposed and hepatocyte death. to a toxic concentration of APAP showed twofold and Calcium deregulation has a profound effect on cell survival greater increases in glycogen phosphorylase a stimulavia numerous signal-transducing pathways utilizing Ca 2/ as tion at 6 hours, which was reversible with Ca 2/ -chelating a second messenger. 4,5 Several mechanisms of cell death have agents. Cell death was preceded by a large decline in been proposed for APAP and other alkylating hepatotoxins. intact, double-stranded DNA. Following toxic adminisSites of Ca 2/ activity include cellular macromolecules directly tration of APAP, the percentage of total double-stranded modified by alkylation. APAP-induced cytotoxicity is associ-DNA was significantly reduced by 2 hours. At 6 and 24 ated with mitochondrial damage, adenosine 5 triphosphate hours, genomic integrity was compromised by 26% and (ATP) depletion, and concomitant increases in adenosine di-37%, respectively, compared with untreated controls.phosphate and adenosine monophosphate. 6 Alternatively, the Hepatotoxic effects of APAP-mediated Ca 2/ deregulation DNA Ca 2/ hypothesis of necrotic cell death states that alkylwere confirmed in both primary mouse hepatocytes and ating hepatotoxins damage DNA in various ways, including the human hepatoblastoma HepG2 cell line by lactate damage by adduct formation and Ca 2/ -endonuclease activad...

show abstract

Immunohistochemical Localization of Acetaminophen in Target Tissues of the CD-1 Mouse: Correspondence of Covalent Binding with Toxicity

Cited by 81 publications

References 0 publications

Olfactory Toxicity of Methimazole: Dose-Response and Structure-Activity Studies and Characterization of Flavin-Containing Monooxygenase Activity in the Long-Evans Rat Olfactory Mucosa

Olfactory Toxicity of Methimazole: Dose-Response and Structure-Activity Studies and Characterization of Flavin-Containing Monooxygenase Activity in the Long-Evans Rat Olfactory Mucosa

In Vivo Mechanisms of Tissue-Selective Drug Toxicity: Effects of Liver-Specific Knockout of the NADPH-Cytochrome P450 Reductase Gene on Acetaminophen Toxicity in Kidney, Lung, and Nasal Mucosa

Calcium-dependent DNA damage and adenosine 3′,5′-cyclic monophosphate- independent glycogen phosphorylase activation in an in vitro model of acetaminophen-induced liver injury

Contact Info

Product

Resources

About