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Arch Toxicol. 2017 Nov;91(11):3647-3662. doi: 10.1007/s00204-017-1994-x. Epub 2017 May 23.

Mechanisms of hepatotoxicity associated with the monocyclic β-lactam antibiotic BAL30072.

Author information

1
Division of Clinical Pharmacology and Toxicology, University Hospital, Hebelstrasse 2, 4031, Basel, Switzerland.
2
Department of Biomedicine, University of Basel, Hebelstrasse 20, 4056, Basel, Switzerland.
3
InSphero AG, Wagistrasse 27, 8952, Schlieren, Switzerland.
4
Basilea Pharmaceutica International Ltd, Grenzacherstrasse 487, 4058, Basel, Switzerland.
5
The Hamner-UNC Institute for Drug Safety Sciences, The Hamner Institute for Health Sciences, Research Triangle Park, NC, USA.
6
The UNC Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, NC, USA.
7
Division of Clinical Pharmacology and Toxicology, University Hospital, Hebelstrasse 2, 4031, Basel, Switzerland. stephan.kraehenbuehl@usb.ch.
8
Department of Biomedicine, University of Basel, Hebelstrasse 20, 4056, Basel, Switzerland. stephan.kraehenbuehl@usb.ch.
9
Swiss Centre of Applied Human Toxicology, Missionsstrasse 64, 4055, Basel, Switzerland. stephan.kraehenbuehl@usb.ch.

Abstract

BAL30072 is a new monocyclic β-lactam antibiotic under development which provides a therapeutic option for the treatment of severe infections caused by multi-drug-resistant Gram-negative bacteria. Despite the absence of liver toxicity in preclinical studies in rats and marmosets and in single dose clinical studies in humans, increased transaminase activities were observed in healthy subjects in multiple-dose clinical studies. We, therefore, initiated a comprehensive program to find out the mechanisms leading to hepatocellular injury using HepG2 cells (human hepatocellular carcinoma cell line), HepaRG cells (inducible hepatocytes derived from a human hepatic progenitor cell line), and human liver microtissue preparations. Our investigations demonstrated a concentration- and time-dependent reduction of the ATP content of BAL30072-treated HepG2 cells and liver microtissues. BAL30072 impaired oxygen consumption by HepG2 cells at clinically relevant concentrations, inhibited complexes II and III of the mitochondrial electron transport chain, increased the production of reactive oxygen species (ROS), and reduced the mitochondrial membrane potential. Furthermore, BAL 30072 impaired mitochondrial fatty acid metabolism, inhibited glycolysis, and was associated with hepatocyte apoptosis. Co-administration of N-acetyl-L-cysteine partially protected hepatocytes from BAL30072-mediated toxicity, underscoring the role of oxidative damage in the observed hepatocellular toxicity. In conclusion, BAL30072 is toxic for liver mitochondria and inhibits glycolysis at clinically relevant concentrations. Impaired hepatic mitochondrial function and inhibition of glycolysis can explain liver injury observed in human subjects receiving long-term treatment with this compound.

KEYWORDS:

Glycolysis; Hepatotoxicity; Mitochondrial toxicity; Monocyclic β-lactams; Reactive oxygen species (ROS)

PMID:
28536862
DOI:
10.1007/s00204-017-1994-x
[Indexed for MEDLINE]

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