Imipramine- and mianserin-induced acute cell injury in primary cultured rat hepatocytes: implication of different cytochrome P450 enzymes

@article{Masubuchi1999ImipramineAM,
  title={Imipramine- and mianserin-induced acute cell injury in primary cultured rat hepatocytes: implication of different cytochrome P450 enzymes},
  author={Yasuhiro Masubuchi and M Konishi and Toshiharu Horie},
  journal={Archives of Toxicology},
  year={1999},
  volume={73},
  pages={147-151}
}
Abstract The antidepressants, imipramine and mianserin, have been reported to cause liver damage. We investigated a role of cytochrome P450 (CYP)-mediated formation of a reactive metabolite in antidepressant-induced acute cell injury using hepatocytes isolated from male and female Wistar rats, and male Dark Agouti rats, which have different relative abundance of CYP enzymes. Culture of the hepatocytes with imipramine and mianserin caused a marked decrease in glutathione followed by protein… Expand
Role of mitochondrial permeability transition in diclofenac‐induced hepatocyte injury in rats
TLDR
The results showed the important role of MPT in pathogenesis of hepatocyte injury induced by diclofenac and its possible contribution to human idiosyncratic hepatotoxicity. Expand
The impact of β-cyclodextrin on biological and chemical properties of mianserin hydrochloride in aqueous solution
Abstract Mianserin hydrochloride (MIA), a drug, which belongs to a group of tetracyclic, noradrenergic and specific serotonergic antidepressants, is one of the commonly used psychotropic drugs.Expand
Utility of human hepatocyte spheroids for evaluation of hepatotoxicity
Drug-induced hepatotoxicity is a common reason for discontinuing the development of candidate clinical drugs. In the present study, we investigated the utility of three-dimensionally cultured humanExpand
Use of micropatterned cocultures to detect compounds that cause drug-induced liver injury in humans.
TLDR
MPCCs showed superiority over conventional short-term cultures for predictions of clinical DILI, and human MPCCs were more predictive for human liabilities than their rat counterparts. Expand
Regioselective biotransformation of CNS drugs and its clinical impact on adverse drug reactions
TLDR
This review focuses on the relationship between regioselectivity in biotransformation and the ADRs of drugs acting on the central nervous system (CNS) and several CNS drugs and toxicants, of which the metabolites play pivotal roles in ADRs. Expand
The Interaction of Heptakis (2,6-di-O-Methyl)-β-cyclodextrin with Mianserin Hydrochloride and Its Influence on the Drug Toxicity
TLDR
Investigations and the characteristics of interaction mechanisms for MIA and the heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) system are contained and the effects of the complexation on MIA cytotoxicity are evaluated. Expand
Sex differences in pharmacokinetics of antidepressants
TLDR
Although the available pharmacokinetic evidence indicates that women should receive lower doses of antidepressants and men should receive higher doses, current guidelines do not recommend dose adjustment, because these sex differences are considered to be clinically insignificant. Expand
The Role of Drug Metabolism in Toxicity
TLDR
The article presents some key characteristics of the common enzymes encountered in metabolic clearance of drugs. Expand
High-throughput screening and characterization of reactive metabolites using polarity switching of hybrid triple quadrupole linear ion trap mass spectrometry.
TLDR
The PI-EPI approach revealed the presence of known adducts and, in many instances, identified additional conjugates that had not been reported previously, in comparison to the widely used neutral loss (NL) scanning analysis. Expand

References

SHOWING 1-10 OF 31 REFERENCES
Formation of cytotoxic metabolites from phenytoin, imipramine, desipramine, amitriptyline and mianserin by mouse and human hepatic microsomes.
TLDR
Analysis of stable metabolites revealed that mianserin is activated to a cytotoxic metabolite selectively by a constitutive form of human cytochrome P-450, whereas phenytoin, amitriptyline and imipramine are selectively activated by forms of mouse cyto Chrome which are induced by either phenobarbitone or beta-naphthoflavone. Expand
Evaluation of the cytotoxicity of tricyclic antidepressants in primary cultures of rat hepatocytes.
TLDR
Primary cultures of hepatocytes from postnatal Sprague-Dawley rats were grown in arginine-deficient, ornithine-supplemented medium to inhibit fibroblastic overgrowth and to selectively isolate relatively pure cultures of parenchymal hepatocytes to evaluate the cytotoxicity of certain tricyclic antidepressant drugs. Expand
Inhibition and induction of cytochrome P450 isozymes after repetitive administration of imipramine in rats.
TLDR
Results indicate that imipramine has two actions on the liver CYP system (i.e. as an inhibitor of the CYP2D enzyme and as a phenobarbital-type inducer). Expand
Alterations in intracellular thiol homeostasis during the metabolism of menadione by isolated rat hepatocytes.
TLDR
The effects of menadione (2-methyl-1,4-naphthoquinone) metabolism on intracellular soluble and protein-bound thiols were investigated in freshly isolated rat hepatocytes and it was suggested that the loss of protein sulfhydryl groups, like that of GSH, was mainly a result of oxidative processes occurring within the cell during the metabolism ofMenadione. Expand
Imipramine-induced inactivation of a cytochrome P450 2D enzyme in rat liver microsomes: in relation to covalent binding of its reactive intermediate.
TLDR
Results suggest that IMI is biotransformed into a chemically reactive metabolite through its 2-hydroxylation step by the CYP2D enzyme in rat liver microsomes, and the metabolite binds covalently to the enzyme itself, resulting in the inactivation. Expand
Activation of mianserin and its metabolites by human liver microsomes.
TLDR
Inhibition of irreversible binding was demonstrated with sodium cyanide at concentrations which did not inhibit total metabolism, which suggest that metabolic activation by the cytochrome P-450 enzyme system may lead to the formation of a reactive iminium intermediate that can bind to nucleophilic groups on proteins. Expand
Evaluation of the involvement of a male specific cytochrome P-450 isozyme in senescence-associated decline of hepatic drug metabolism in male rats.
TLDR
This study provides the first direct evidence that differences in the amount of the major male specific P-450 isozyme (P-450ml) are responsible for the age- and sex-associated differences in some of the drug metabolizing activities. Expand
Regioselective contribution of the cytochrome P-450 2D subfamily to propranolol metabolism in rat liver microsomes.
TLDR
Results indicate that a polymorphic cytochrome P-450 isozyme(s) belonging to the CYP2D subfamily is involved predominantly in propranolol 4, 5, and 7-hydroxylations at low substrate concentrations in the rat. Expand
SPECIES DIFFERENCES IN THE METABOLISM OF IMIPRAMINE AND DESMETHYLIMIPRAMINE (DMI).
TLDR
Evidence presented in this paper indicates that differences in the metabolism of imipramine and DMI may partially explain the species variations in the pharmacologic response of these "antisedative" compounds. Expand
Irreversible protein binding of [14-C]imipramine with rat and human liver microsomes.
TLDR
The results favour the concept that irreversible protein binding of imipramine is catalyzed by a cytochrome P-450-dependent hydroxylation via an epoxidation step. Expand
...
1
2
3
4
...