Investigating the in vitro steatotic mixture effects of similarly and dissimilarly acting test compounds using an adverse outcome pathway-based approach

Alarcan, Jimmy; Sousa, Georges de; Katsanou, Efrosini S.; Spyropoulou, Anastasia; Batakis, Petros; Machera, Kyriaki; Rahmani, Roger; Lampen, Alfonso; Braeuning, Albert; Lichtenstein, Dajana

doi:10.1007/s00204-021-03182-1

Cited by 9 publications

(4 citation statements)

References 33 publications

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“…This first AOP was taken as a starting point, and other NRs were incorporated as MIEs as well [88][89][90][91][92][93][94]. Presently, most, if not all AOPs for steatosis in AOP-Wiki identify a NR or another TF as the MIE.…”

Section: Consistency Of Identified Difld Mechanisms With Current Adve...mentioning

confidence: 99%

Drug-Induced Fatty Liver Disease (DIFLD): A Comprehensive Analysis of Clinical, Biochemical, and Histopathological Data for Mechanisms Identification and Consistency with Current Adverse Outcome Pathways

López-Pascual,

Rienda,

Perez-Rojas

et al. 2024

IJMS

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Drug induced fatty liver disease (DIFLD) is a form of drug-induced liver injury (DILI), which can also be included in the more general metabolic dysfunction-associated steatotic liver disease (MASLD), which specifically refers to the accumulation of fat in the liver unrelated to alcohol intake. A bi-directional relationship between DILI and MASLD is likely to exist: while certain drugs can cause MASLD by acting as pro-steatogenic factors, MASLD may make hepatocytes more vulnerable to drugs. Having a pre-existing MASLD significantly heightens the likelihood of experiencing DILI from certain medications. Thus, the prevalence of steatosis within DILI may be biased by pre-existing MASLD, and it can be concluded that the genuine true incidence of DIFLD in the general population remains unknown. In certain individuals, drug-induced steatosis is often accompanied by concomitant injury mechanisms such as oxidative stress, cell death, and inflammation, which leads to the development of drug-induced steatohepatitis (DISH). DISH is much more severe from the clinical point of view, has worse prognosis and outcome, and resembles MASH (metabolic-associated steatohepatitis), as it is associated with inflammation and sometimes with fibrosis. A literature review of clinical case reports allowed us to examine and evaluate the clinical features of DIFLD and their association with specific drugs, enabling us to propose a classification of DIFLD drugs based on clinical outcomes and pathological severity: Group 1, drugs with low intrinsic toxicity (e.g., ibuprofen, naproxen, acetaminophen, irinotecan, methotrexate, and tamoxifen), but expected to promote/aggravate steatosis in patients with pre-existing MASLD; Group 2, drugs associated with steatosis and only occasionally with steatohepatitis (e.g., amiodarone, valproic acid, and tetracycline); and Group 3, drugs with a great tendency to transit to steatohepatitis and further to fibrosis. Different mechanisms may be in play when identifying drug mode of action: (1) inhibition of mitochondrial fatty acid β-oxidation; (2) inhibition of fatty acid transport across mitochondrial membranes; (3) increased de novo lipid synthesis; (4) reduction in lipid export by the inhibition of microsomal triglyceride transfer protein; (5) induction of mitochondrial permeability transition pore opening; (6) dissipation of the mitochondrial transmembrane potential; (7) impairment of the mitochondrial respiratory chain/oxidative phosphorylation; (8) mitochondrial DNA damage, degradation and depletion; and (9) nuclear receptors (NRs)/transcriptomic alterations. Currently, the majority of, if not all, adverse outcome pathways (AOPs) for steatosis in AOP-Wiki highlight the interaction with NRs or transcription factors as the key molecular initiating event (MIE). This perspective suggests that chemical-induced steatosis typically results from the interplay between a chemical and a NR or transcription factors, implying that this interaction represents the primary and pivotal MIE. However, upon conducting this exhaustive literature review, it became evident that the current AOPs tend to overly emphasize this interaction as the sole MIE. Some studies indeed support the involvement of NRs in steatosis, but others demonstrate that such NR interactions alone do not necessarily lead to steatosis. This view, ignoring other mitochondrial-related injury mechanisms, falls short in encapsulating the intricate biological mechanisms involved in chemically induced liver steatosis, necessitating their consideration as part of the AOP’s map road as well.

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Section: Consistency Of Identified Difld Mechanisms With Current Adve...mentioning

confidence: 99%

Drug-Induced Fatty Liver Disease (DIFLD): A Comprehensive Analysis of Clinical, Biochemical, and Histopathological Data for Mechanisms Identification and Consistency with Current Adverse Outcome Pathways

López-Pascual,

Rienda,

Perez-Rojas

et al. 2024

IJMS

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“…On the other hand, mixtures of chemicals with different modes of action are usually characterized by the independent action (IA) model (Cedergreen et al, 2008). However, it was shown that even binary and ternary mixtures of compounds with dissimilar modes of action induced triglyceride accumulation in a CA manner (Alarcan et al, 2022). In practice, CA model which generates more conservative predictions is usually the default recommended model for risk assessment (Cedergreen, 2014).…”

Section: Introductionmentioning

confidence: 99%

Estrogenic Potency of Endocrine Disrupting Chemicals and Their Mixtures Detected in Environmental Waters and Wastewaters

Durcik

Grobin

Roškar

et al. 2023

Preprint

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“…The project strongly relied on adverse outcome pathways (AOP) and thus in turn substance interactions such as for example the ability of a test compound to interact with certain molecular targets and exert toxicological effects. As a consequence mixture selection in “EuroMix” was essentially based on the toxicodynamic properties of the individual test chemicals (Alarcan et al 2021 ; Beronius et al 2020 ). This is also further substantiated in the recent European Food Safety Authority (EFSA) Mixtox Guidance (EFSA 2021 ).…”

Section: Introductionmentioning

confidence: 99%

An approach for mixture testing and prioritization based on common kinetic groups

et al. 2022

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In light of an ever-increasing exposure to chemicals, the topic of potential mixture toxicity has gained increased attention, particularly as the toxicological toolbox to address such questions has vastly improved. Routinely toxicological risk assessments will rely on the analysis of individual compounds with mixture effects being considered only in those specific cases where co-exposure is foreseeable, for example for pesticides or food contact materials. In the field of pesticides, active substances are summarized in so-called cumulative assessment groups (CAG) which are primarily based on their toxicodynamic properties, that is, respective target organs and mode of action (MoA). In this context, compounds causing toxicity by a similar MoA are assumed to follow a model of dose/concentration addition (DACA). However, the respective approach inherently falls short of addressing cases where there are dissimilar or independent MoAs resulting in wider toxicokinetic effects. Yet, the latter are often the underlying cause when effects deviate from the DACA model. In the present manuscript, we therefore suggest additionally to consider toxicokinetic effects (especially related to xenobiotic metabolism and transporter interaction) for the grouping of substances to predict mixture toxicity. In line with the concept of MoA-based CAGs, we propose common kinetics groups (CKGs) as an additional tool for grouping of chemicals and mixture prioritization. Fundamentals of the CKG concept are discussed, along with challenges for its implementation, and methodological approaches and examples are explored.

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Investigating the in vitro steatotic mixture effects of similarly and dissimilarly acting test compounds using an adverse outcome pathway-based approach

Cited by 9 publications

References 33 publications

Drug-Induced Fatty Liver Disease (DIFLD): A Comprehensive Analysis of Clinical, Biochemical, and Histopathological Data for Mechanisms Identification and Consistency with Current Adverse Outcome Pathways

Drug-Induced Fatty Liver Disease (DIFLD): A Comprehensive Analysis of Clinical, Biochemical, and Histopathological Data for Mechanisms Identification and Consistency with Current Adverse Outcome Pathways

Estrogenic Potency of Endocrine Disrupting Chemicals and Their Mixtures Detected in Environmental Waters and Wastewaters

An approach for mixture testing and prioritization based on common kinetic groups

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