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

Abstract

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.

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

“…ethyl]amino]-1,2,3,4,7,12-hexahydronaphto- [2,3]-quinoxaline-7-12-dione), which has proven antitumour effects and has been related to MTX toxicity [5,10]. Recently, we demonstrated that, as it happens with MTX, the naphthoquinoxaline metabolite also distributes to highly perfused tissues and accumulates in organs such as liver and heart in rats [5].…”

“…Recently, we demonstrated that, as it happens with MTX, the naphthoquinoxaline metabolite also distributes to highly perfused tissues and accumulates in organs such as liver and heart in rats [5]. The liver is subjected to a prolonged exposure to MTX and, possibly, to this toxic metabolite that may contribute to its direct hepatotoxicity.…”

“…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].…”

Highlight report: metabolism and toxicity by fumonisins

“…Nevertheless, fumonisins have attracted relatively little attention in toxicological research. Currently, hepatotoxicity (Campos et al 2014;Liu et al 2014;Godoy et al 2009Godoy et al , 2013Godoy et al , 2015Schyschka et al 2013;Schliess et al 2014;Grinberg et al 2014), nephrotoxicity (Yang et al 2014;Yu et al 2013;Early et al 2013;Kitada et al 2006;Ruíz-López et al 2006;Bulacio and Torres 2013) and cardiotoxicity (Fujisawa et al 2014;Maayah et al 2014;Ferreiro et al 2014;Rossato et al 2013) represent cutting-edge topics in toxicology. Recently, lists of reference compounds have been recommended for establishment of in vitro systems of repeated dose toxicity (Jennings et al 2014;Hengstler et al 2014).…”

In vitro systems: current limitations and future perspectives

“…Moreover, zebrafish-based test systems have been studied as an alternative method to identify hepatotoxic compounds (Driessen et al 2013;Scholz 2013). Compared to the high number of studies based on in vitro systems the fraction of in vivo studies published in the Archives of Toxicology has become relatively small (Rossato et al 2013;Yu et al 2013;Early et al 2013;Cordova et al 2013;Saito et al 2013;Hammad et al 2014). Moreover, studies systematically comparing the functions of in vitro systems to the in vivo situation are rare Heise et al 2012).…”