The role of reductive and oxidative metabolism in the toxicity of mitoxantrone, adriamycin and menadione in human liver derived Hep G2 hepatoma cells

Duthie, Susan J.; Grant, M.H.

doi:10.1038/bjc.1989.314

Cited by 41 publications

(30 citation statements)

References 33 publications

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“…MTX has particular effectiveness in tumors with high contents of peroxidases (Brück and Brück 2011;Blanz et al 1991), and it was verified that the inhibitory effect of MTX on cell growth was prevented by inhibiting the activity of cytochrome P450 mixed oxidase function in a human hepatoma-derived cell line (Duthie and Grant 1989). Similar results were obtained with a rat hepatocytes model (Mewes et al 1993) and with human breast cancer cells (Li et al 1995).…”

Section: Introductionsupporting

confidence: 73%

“…The CYP450 inhibitor MTP (0.5 mM) (Duthie and Grant 1989;Mewes et al 1993;Li et al 1995) and the CYP2E1 subtype inhibitor DAS (150 lM) (Pontes et al 2010) were co-incubated with MTX (100 nM and 1 lM) at 37°C for 96-h. MTP was dissolved in DMSO; thus, a group with only the vehicle (DMSO 0.1 %) was also included. The potential protective effect of metabolism inhibitors in the cytotoxicity of MTX was assessed through the MTT assay.…”

Section: Comparison Of the Cytotoxic Effects Of Non-metabolized Mtx Amentioning

confidence: 99%

“…The metabolism of MTX involves the oxidation through the microsomal system and/or peroxidase enzymes such as neutrophil myeloperoxidase (Duthie and Grant 1989;Panousis et al 1997). Moreover, the phase II metabolism has a relevant role in the MTX detoxification process, namely the conjugation with reduced glutathione (GSH) and glucuronic acid (Ehninger et al 1990).…”

Section: Introductionmentioning

confidence: 99%

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The metabolic profile of mitoxantrone and its relation with mitoxantrone-induced cardiotoxicity

et al. 2013

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Mitoxantrone (MTX) is an antitumor agent that causes cardiotoxicity in 18 % patients. The metabolic profile of MTX was assessed after incubation of 100 lM MTX with hepatic S9 fraction isolated from rats. The presence of MTX and its metabolites was also assessed in vivo through the analysis of liver and heart extracts of MTX-treated rats. The cytotoxic effects of MTX and MTX metabolites were evaluated in the H9c2 cells after 24-h incubation with MTX alone and MTX ? metabolites. The influence of CYP450-and CYP2E1-mediated metabolism for the cytotoxicity of MTX was assessed after 96-h incubation with MTX (100 nM and 1 lM) in the presence/ absence of CYP450 or CYP2E1 inhibitors. After 4-h incubation in supplemented S9 fraction, the MTX content was 35 % lower and 5 metabolites were identified: an acetoxy ester derivative (never described before), two glutathione conjugates, a monocarboxylic acid derivative, and the naphtoquinoxaline, the later commonly related to MTX pharmacological effects. The presence of MTX and naphtoquinoxaline metabolite was evidenced in vivo in liver and heart of MTX-treated rats. The cytotoxicity caused by MTX ? metabolites was higher than that observed in the H9c2 cells incubated with non-metabolized MTX group. The co-incubation of MTX with CYP450 and CYP2E1 inhibitors partially prevented the cytotoxicity observed in the MTX groups incubated with H9c2 cells, highlighting that the metabolism of MTX is relevant for its undesirable effects. The naphtoquinoxaline metabolite is described in heart and liver in vivo, highlighting that this metabolite accumulates in these tissues. It was demonstrated that MTX P450-mediated metabolism contributed to MTX toxicity.

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Section: Introductionsupporting

confidence: 73%

Section: Comparison Of the Cytotoxic Effects Of Non-metabolized Mtx Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The metabolic profile of mitoxantrone and its relation with mitoxantrone-induced cardiotoxicity

et al. 2013

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“…The apparent contradiction between our results (increased in the GSH hepatic levels) and the previously reported data (decreases in the GSH content) may be explained by the differences in the experimental design or models. Both referred studies assessed the GSH levels 3, 4 and 5 days after MTX administration [9] or 6 hr after high MTX concentration incubation [30]. In the present study, significant changes in the glutathione sta-tus were seen only at the last evaluated time-point, 28 days after the last dose administration.…”

Section: Discussionmentioning

confidence: 47%

“…The link between oxidative stress and the MTX-induced hepatic damage was already suggested in a study with mice, where the administration of MTX (15 mg/kg) caused increases in the lipid peroxidation, decreases in the antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) and depletion of the hepatic retinol and GSH content [9]. Moreover, the incubation of MTX (100 lM) with HepG2 cells for 6 hr was enough to promote the decrease in the GSH levels [30]. The apparent contradiction between our results (increased in the GSH hepatic levels) and the previously reported data (decreases in the GSH content) may be explained by the differences in the experimental design or models.…”

Section: Discussionmentioning

confidence: 97%

Cumulative Mitoxantrone‐Induced Haematological and Hepatic Adverse Effects in a Subchronic In vivo Study

Rossato

Costa

Dallegrave

et al. 2013

Basic Clin Pharma Tox

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Mitoxantrone (MTX) is an antineoplastic agent that can induce hepato-and haematotoxicity. This work aimed to investigate the occurrence of cumulative early and late MTX-induced hepatic and haematological disturbances in an vivo model. A control group and two groups treated with three cycles of 2.5 mg/kg MTX at days 0, 10 and 20 were formed. One of the treated groups suffered euthanasia on day 22 (MTX22) to evaluate early MTX toxic effects, while the other suffered euthanasia on day 48 (MTX48), to allow the evaluation of MTX late effects. An early immunosuppression with a drop in the IgG levels was observed, causing a slight decrease in the plasma total protein content. The early bone marrow depression was followed by signs of recovery in MTX48. The genotoxic potential of MTX was demonstrated by the presence of several micronuclei in MTX22 leucocytes. Increases in plasma iron and cholesterol levels in the MTX22 rats were observed, while in both groups increases in the unconjugated bilirubin, C4 complement, and decreases in the triglycerides, alanine aminotransferase, alkaline phosphatase and transferrin were found in plasma samples. On MTX 48, the liver histology showed more hepatotoxic signs, the hepatic levels of reduced and oxidized glutathione were increased, and ATP hepatic levels were decreased. However, the hepatic total protein levels were decreased only in the livers of MTX22 group. Results demonstrated the MTX genotoxic effects, haemato-and direct hepatotoxicity. While the haematological toxicity is ameliorated with time, the same was not observed in the hepatic injury.Mitoxantrone (MTX) is an anticancer and immunosuppressive drug that has been used in the treatment of tumours such as acute leukaemia, lymphoma, prostatic and breast cancer [1] and in the active forms of relapsing-remitting or secondary progressive multiple sclerosis [2]. MTX acts as an intercalating agent that causes double breaks in DNA by stabilization of a complex formed between DNA and topoisomerase II [1,3]. The regimen of MTX administration varies depending on disease progression and the clinical condition of the patient. Additionally, MTX is a substrate of membrane efflux pumps, namely the transporter breast cancer resistance protein (BCRP), which could interfere in MTX biodisposition [4]. However, the doses commonly employed range between 12-14 mg/m 2 and the maximum recommended cumulative dose is 140 mg/m 2 [1].One of the most serious adverse events related to MTX therapy is the late and irreversible cardiotoxicity [1], whose underlying mechanisms have been studied by us [5][6][7]. It is known that cardiotoxic drugs such as MTX can cause acute liver failure as a result of a primary congestive heart failure with low cardiac output and consequent reduced hepatic blood flow [8]. However, the precise origin of liver failure, due to a direct effect or secondary to the cardiomyopathy, is not easy to define, because clinical signs of cardiac decompensating can be undetected in a first moment delaying the diagnosis [8]. Additi...

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Anthracene-1,4,9,10-tetraone Derivatives: Synthesis and Antitumor Activity

Jin¹,

Kim²,

Chung³

et al. 1998

Arch. Pharm. Pharm. Med. Chem.

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A series of 2‐alkylated anthracene‐1,4,9,10‐tetraone (ATO) derivatives were synthesized, and their antitumor action in ICR mice bearing S‐180 cells and antiproliferative activity against L1210 cells were evaluated. Overall, the introduction of an alkyl group (C1–C8) at C‐2 enhanced the antiproliferative activity. Among 2‐(1‐hydroxyalkyl)‐ or 2‐(1‐acetoxyalkyl)‐ATO derivatives, four compounds possessing alkyl chain of an intermediate size (C4–C6) gave T/C values of > 300%. Acetylation at 1′‐OH failed to cause an enhancement in the antitumor action, in contrast to a remarkable increase in antiproliferative activity. Although there was no direct relationship between antiproliferative activity and antitumor action, the compounds with lower antiproliferative activity tended to show higher antitumor activity. Further study shows that the antiproliferative activity of ATO derivatives may be explained properly neither by redox cycling nor arylating capacity.

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The role of reductive and oxidative metabolism in the toxicity of mitoxantrone, adriamycin and menadione in human liver derived Hep G2 hepatoma cells

Cited by 41 publications

References 33 publications

The metabolic profile of mitoxantrone and its relation with mitoxantrone-induced cardiotoxicity

The metabolic profile of mitoxantrone and its relation with mitoxantrone-induced cardiotoxicity

Cumulative Mitoxantrone‐Induced Haematological and Hepatic Adverse Effects in a Subchronic In vivo Study

Anthracene-1,4,9,10-tetraone Derivatives: Synthesis and Antitumor Activity

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