Formation of GSH-trapped reactive metabolites in human liver microsomes, S9 fraction, HepaRG-cells, and human hepatocytes

Lassila, Toni; Rousu, Timo; Mattila, Sampo; Chesné, Christophe; Pelkonen, Olavi; Turpeinen, Miia; Tolonen, Ari

doi:10.1016/j.jpba.2015.07.020

Cited by 18 publications

(13 citation statements)

References 32 publications

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“…An external calibration system was used, and the data was processed using Thermo Xcalibur (version 4.1.31.9; Thermo Fisher Scientific Inc.). 52 Estimation of Kinetic and Inhibition Properties. Because of their high hydrolytic activity, corneal and retinal samples from pig and rabbit were used to determine the apparent kinetic parameters Michaelis−Menten constant (K m ) and maximum reaction velocity (V max ) for the hydrolysis of NPA, FDA, and DME.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Carboxylesterase Activities and Protein Expression in Rabbit and Pig Ocular Tissues

et al. 2021

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Hydrolytic reactions constitute an important pathway of drug metabolism and a significant route of prodrug activation. Many ophthalmic drugs and prodrugs contain ester groups that greatly enhance their permeation across several hydrophobic barriers in the eye before the drugs are either metabolized or released, respectively, via hydrolysis. Thus, the development of ophthalmic drug therapy requires the thorough profiling of substrate specificities, activities, and expression levels of ocular esterases. However, such information is scant in the literature, especially for preclinical species often used in ophthalmology such as rabbits and pigs. Therefore, our aim was to generate systematic information on the activity and expression of carboxylesterases (CESs) and arylacetamide deacetylase (AADAC) in seven ocular tissue homogenates from these two species. The hydrolytic activities were measured using a generic esterase substrate (4-nitrophenyl acetate) and, in the absence of validated substrates for rabbit and pig enzymes, with selective substrates established for human CES1, CES2, and AADAC ( d -luciferin methyl ester, fluorescein diacetate, procaine, and phenacetin). Kinetics and inhibition studies were conducted using these substrates and, again due to a lack of validated rabbit and pig CES inhibitors, with known inhibitors for the human enzymes. Protein expression levels were measured using quantitative targeted proteomics. Rabbit ocular tissues showed significant variability in the expression of CES1 (higher in cornea, lower in conjunctiva) and CES2 (higher in conjunctiva, lower in cornea) and a poor correlation of CES expression with hydrolytic activities. In contrast, pig tissues appear to express only CES1, and CES3 and AADAC seem to be either low or absent, respectively, in both species. The current study revealed remarkable species and tissue differences in ocular hydrolytic enzymes that can be taken into account in the design of esterase-dependent prodrugs and drug conjugates, the evaluation of ocular effects of systemic drugs, and in translational and toxicity studies.

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Section: ■ Materials and Methodsmentioning

confidence: 99%

Carboxylesterase Activities and Protein Expression in Rabbit and Pig Ocular Tissues

et al. 2021

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“…Carboxylic acid metabolites of dechlorinatedterbuthylazine in groundwater may be conjugated by UDP-glucuronosyl transferases (UGTs) to yield acyl glucuronides. These are linked to idiosyncratic drug toxicities and can be found in pharmaceuticals at relatively high (clinical) doses [ 39 , 40 ]. Regarding triazines, kidney damage has been observed in several 90-day rat studies on terbuthylazine and other triazines, but kidney damage is possibly due to the physicochemical nature of triazine metabolites and their precipitation in the kidneys at high doses [ 41 ].…”

Section: Toxicokinetics Of Chloro-s-triazinesmentioning

confidence: 99%

“…However, on the basis of in vitro studies, it is practically impossible to suggest that glutathione conjugates predict reactive metabolite-based toxic reactions. This is because the nature and quantity of specific GSH-conjugates are dependent on the substance under study and on the specific in vitro systems used [ 39 , 45 ]. Toxicological studies on atrazine or other triazines do not suggest potentially reactive metabolite-associated toxic outcomes.…”

Section: Toxicokinetics Of Chloro-s-triazinesmentioning

confidence: 99%

Chloro-s-triazines-toxicokinetic, Toxicodynamic, Human Exposure, and Regulatory Considerations

Abass

Pelkonen

Rautio

2021

CDM

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: Chloro-s-triazenes - atrazine, cyanazine, propazine, simazine, and terbuthylazine - are structurally similar herbicides, differing only in specific s-triazine 4- and 6-N alkyl substituents. It is generally regarded that their toxicokinetics, including metabolic pathways, biological effects and toxicities, also share more similar features than differences. Consequently, it is useful to compare their characteristics to potentially find useful structure-activity relationships or other similarities or differences regarding different active compounds, their metabolites, and biological effects, including toxic outcomes. The ultimate goal of these exercises is to apply the knowledge summarized, as far as it is possible regarding a patchy and often inadequate database, to cross the in vitro-in vivo and animal-human borders and integrate the available data to enhance toxicological risk assessment for the benefit of humans and ecosystems.

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“…Higher doses of peppermint oil, in which PUL is one of the active constituents, caused a decrease in human hepatoma HG2P128 cells’ viability in vitro [ 21 ]. In human hepatocytes and HepaRG cells, PUL was shown to produce glutathione-trapped reactive metabolites, which may be responsible for its idiosyncratic toxicity [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Inter-Individual Variability in Acute Toxicity of R-Pulegone and R-Menthofuran in Human Liver Slices and Their Influence on miRNA Expression Changes in Comparison to Acetaminophen

Zárybnický

Matoušková

Lancošová

et al. 2018

IJMS

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Monoterpenes R-pulegone (PUL) and R-menthofuran (MF), abundant in the Lamiaceae family, are frequently used in herb and food products. Although their hepatotoxicity was shown in rodent species, information about their effects in human liver has been limited. The aim of our study was to test the effects of PUL, MF and acetaminophen (APAP, as a reference compound) on cell viability and microRNA (miRNA) expression in human precision-cut liver slices. Slices from five patients were used to follow up on the inter-individual variability. PUL was toxic in all liver samples (the half-maximal effective concentration was 4.0 µg/mg of tissue), while MF and surprisingly APAP only in two and three liver samples, respectively. PUL also changed miRNA expression more significantly than MF and APAP. The most pronounced effect was a marked decrease of miR-155-5p expression caused by PUL even in non-toxic concentrations in all five liver samples. Our results showed that PUL is much more toxic than MF and APAP in human liver and that miR-155-5p could be a good marker of PUL early hepatotoxicity. Marked inter-individual variabilities in all our results demonstrate the high probability of significant differences in the hepatotoxicity of tested compounds among people.

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Formation of GSH-trapped reactive metabolites in human liver microsomes, S9 fraction, HepaRG-cells, and human hepatocytes

Cited by 18 publications

References 32 publications

Carboxylesterase Activities and Protein Expression in Rabbit and Pig Ocular Tissues

Carboxylesterase Activities and Protein Expression in Rabbit and Pig Ocular Tissues

Chloro-s-triazines-toxicokinetic, Toxicodynamic, Human Exposure, and Regulatory Considerations

Inter-Individual Variability in Acute Toxicity of R-Pulegone and R-Menthofuran in Human Liver Slices and Their Influence on miRNA Expression Changes in Comparison to Acetaminophen

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