Increase, Mitochondrial complex III antagonism

1397-94-0

Antimycin A

Antipiricullin Fintrol Virosin

DTXSID9032325

1951-25-3

IYIKLHRQXLHMJQ-UHFFFAOYSA-N

Amiodarone

Methanone, (2-butyl-3-benzofuranyl)[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]- 2-Butyl-3-[3,5-diiodo-4-(2-diethylaminoethoxy)benzoyl]benzofuran 2-Butyl-3-benzofuranyl p-[(2-diethylamino)ethoxy]-m,m-diiodophenyl ketone 2-n-Butyl-3',5'-diiodo-4'-N-diethylaminoethoxy-3-benzoylbenzofuran Amidorone Amiodaron amiodarona Ancaron Ketone, 2-butyl-3-benzofuranyl 4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl Sedacoron Sedacorone

DTXSID7022592

3562-84-3

WHQCHUCQKNIQEC-UHFFFAOYSA-N

Benzbromarone

DTXSID4022652

51-28-5

UFBJCMHMOXMLKC-UHFFFAOYSA-N

2,4-Dinitrophenol

DNP 1,3-Dinitro-4-hydroxybenzene 1-Hydroxy-2,4-dinitrobenzene 2,4-dinitrofenol Aldifen Dinitrophenol DINITROPHENOL, 2,4- Dinofan Fenoxyl Carbon N NSC 1532 Phenol, α-dinitro- UN 1320 UN 1599 α-Dinitrophenol Phenol, 2,4-dinitro-

DTXSID0020523

10537-47-0

MZOPWQKISXCCTP-UHFFFAOYSA-N

Malonoben

DTXSID1042106

87-86-5

IZUPBVBPLAPZRR-UHFFFAOYSA-N

Pentachlorophenol

PCP Phenol, pentachloro- 1-Hydroxy-2,3,4,5,6-pentachlorobenzene 1-Hydroxypentachlorobenzene Chlorophenasic acid CHLOROPHENATE Dowicide EC 7 Dura Treet II Fungifen Grundier Arbezol Lauxtol Liroprem NSC 263497 Penchlorol Pentachlorphenol Perchlorophenol Permasan Phenol, 2,3,4,5,6-pentachloro- Pole topper Pole topper fluid Preventol P Santophen 20 Satophen UN 3155 Witophen P Woodtreat A 2,3,4,5,6-Pentachlorophenol

DTXSID7021106

3380-34-5

XEFQLINVKFYRCS-UHFFFAOYSA-N

Triclosan

5-Chloro-2-(2,4-dichlorophenoxy)phenol Phenol, 5-chloro-2-(2,4-dichlorophenoxy)- 2, 4, 4'-Trichloro-2'-hydroxydiphenylether 2,2'-Oxybis(1',5'-dichlorophenyl-5-chlorophenol) 2,4,4'-TRICHLORO-2'-HYDROXY DIPHENYLETHER 2',4',4-Trichloro-2-hydroxydiphenyl ether 2',4,4'-Trichloro-2-hydroxydiphenyl ether 2,4,4'-Trichloro-2'-hydroxydiphenyl ether 2'-Hydroxy-2,4,4'-trichlorodiphenyl ether 2-Hydroxy-2',4,4'-trichlorodiphenyl ether 3-Chloro-6-(2,4-dichlorophenoxy)phenol 4-Chloro-2-hydroxyphenyl 2,4-dichlorophenyl ether 5-Chloro-2-(2', 4'-dichlorophenoxy) phenol Aquasept Bacti-Stat soap Cansan TCH DIPHENYL ETHER, 2,4,4'-TRICHLORO-2'-HYDROXY- Irgacare MP Irgacide LP 10 Irgaguard B 1000 Irgaguard B 1325 Irgasan Irgasan CH 3565 Irgasan DP 30 Irgasan DP 300 Irgasan DP 3000 Irgasan DP 400 Irgasan PE 30 Irgasan PG 60 Microban Additive B Microban B Oletron Phenol, 5-chloro-2-(2,4-dichlorophenoxy) Phenol, 5-chloro-2-(2,4-dichlorophenoxy)-, dihydrogen phosphate Sanitized XTX Sapoderm SterZac Tinosan AM 100 Tinosan AM 110 TRICLOSAM Ultra Fresh NM 100 Ultrafresh NM-V 2 Vinyzene DP 7000 Yujiexin Zilesan UW

DTXSID5032498

518-82-1

RHMXXJGYXNZAPX-UHFFFAOYSA-N

Emodin

9,10-Anthracenedione, 1,3,8-trihydroxy-6-methyl- 1,3,8-trihidroxi-6-metilantraquinona 1,3,8-Trihydroxy-6-methyl-9,10-anthraquinone 1,3,8-Trihydroxy-6-methylanthrachinon 1,3,8-trihydroxy-6-methylanthraquinone 1,6,8-Trihydroxy-3-methylanthraquinone 3-Methyl-1,6,8-trihydroxyanthraquinone 4,5,7-Trihydroxy-2-methylanthraquinone Anthraquinone, 1,3,8-trihydroxy-6-methyl- Frangula emodin Frangulic acid NSC 408120 NSC 622947 Rheum emodin Schuttgelb

DTXSID5025231

CHEBI:15422

CHEBI ATP

GO:0005623

GO cell

UBERON:0000468

UBERON multicellular organism

GO:0006754

GO ATP biosynthetic process

GO:0008283

GO cell proliferation

GO:0040007

GO growth

WIKI decreased

Antimycin A

2018-12-19T09:50:21

Amiodarone

2016-11-29T18:42:27

Benzbromarone

2019-03-07T05:10:21

Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone

2020-11-12T17:59:28

Carbonyl cyanide m-chlorophenyl hydrazone

2020-11-12T17:59:47

2,4-Dinitrophenol

2016-11-29T18:42:27

Malonoben

2020-11-27T14:43:47

Pentachlorophenol

2020-11-12T17:59:12

Triclosan

2020-11-12T18:00:07

Emodin

2020-11-20T13:48:58

WCS_7955

common ecological species zebrafish

WCS_9606

common toxicological species human

10116

NCBI rat

10090

NCBI mouse

WCS_90988

common ecological species fathead minnow

WCS_4472

common ecological species Lemna minor

WCS_35525

common ecological species Daphnia magna

WCS_7955

common ecological species Danio rerio

Increase, Mitochondrial complex III antagonism

Molecular

The mitochondrial complex III (mitochondrial cytochrome bc1 complex) is an enzyme complex located in the inner membrane of mitochondria. It is the third out of 5 complexes that together form the mitochondrial respiratory chain. It consists out of multiple subunits, including cytochrome b/b6, cytochrome c1 and an 2Fe-2S cluster. The combination of these subunits catalyze following process: <ol> <li> The cytochrome c1 is involved in the process of oxidizing ubiquinol (coming directly from complex I, from complex I via complex II or from complex II) to a semiquinone radical and back to quinone. A process that results in two free electrons that are transferred via cytochrome c to next complex. </li> </ol>   The electron transfer in this process mediates the translocation of protons from the mitochondrial matrix through the inner membrane to the intermembrane space. The created proton gradient will be used to catalyze the reaction in which ADP is converted into ATP.   The initiation event is the reversibly or irreversibly interaction to any of the subunits in the mitochondrial complex III, leading to an perturbation of the electron flow and an absence of proton transport via this complex.

Complex inhibition assays specifically for complex III It is important to release that the activity of complex II depends on the input from complex II. So screening of effects at complex II is advised. The assay exist in multiple forms. Some assay can be performed on whole cells and other needed complex isolation based on antibody interactions. However, they all rely on the following detection of complex II/III activity: The reduction of cytochrome c, which has an absorbance at 550nm. Mitochondrial Membrane potential using fluorescent dyes. Positive charged molecules will accumulated in the mitochondria in an inverse proportion as the membrane potential. More polarised mitochondria will accumulate more dye (Rhodamine123, TMRE, TMRM) - leading to a higher fluorescent signal - and the absence of membrane potential leads to an absence of fluorescent signal. An exception is the dye JC1, because this dye has green fluorescence when present in low concentrations (depolarisation) and red fluorescence when accumulated (hyperpolarized)   Measurements Complex inhibition assays <ol> <li> Cayman MitoCheck MitoCheck® Complex II/III Activity Assay Kit (Item No. 700950) </li> <li> Abcam MitoTox™ Complex II + III OXPHOS Activity Assay Kit (ab109905) </li> <li> BioVision Mitochondrial Complex III Activity Assay Kit (K520) </li> </ol> Membrane potential dyes <ol start="4"> <li> Perry, 2011, mitochondrial membrane potential probes and proton gradient </li> <li> Mitra, 2010, analysis of mitochondrial dynamics and functions using imaging approaches </li> </ol>

AOPWiki 2018-12-19T09:35:55

2020-12-04T17:24:45

Decrease, Adenosine triphosphate pool

Decrease, ATP pool

Cellular

Decreased adenosine triphosphate (ATP) pool describes the loss of balance between ATP synthesis and ATP consumption, leading to reduced total ATP. As a primary form of biological energy, ATP is used by many biological processes (Bonora 2012). Decrease in ATP level normally attributes to metabolic disorders in major ATP synthetic pathways, such as mitochondrial oxidative phosphorylation, fatty acid β-oxidation, glycolysis and plant photophosphorylation.

-The ATP pool in cells or tissue can be quantified using a well-established ATP bioluminescent assay (Lemasters 1978; Wibom 1990). Assay principles: ATP can react with luciferase and luciferin from firefly and the luminescence emitted from the reaction is proportional to the ATP concentration:   ATP + D-Luciferin + O2 è Oxyluciferin + AMP + PPi + CO2 + Light -ToxCast high-throughput screening bioassays, such as “NCCT_HEK293T_CellTiterGLO” and “NIS_HEK293T_CTG_Cytotoxicity” can be used to measure this KE.

Taxonomic applicability domain This key event is in general considered applicable to all eukaryotes utilizing ATP as a direct source of energy and signaling molecule.   Life stage applicability domain This key event is considered applicable to all life stages, as all developmental stages require energy supply to maintain necessary physiological processes.   Sex applicability domain This key event is considered sex-unspecific, as both males and females use ATP as an essential energy molecule.

CL:0000000

CL cell

High Unspecific

High

Embryo

High

Juvenile

Moderate

Adult, reproductively mature

High High High High

Bonora M, Patergnani S, Rimessi A, De Marchi E, Suski JM, Bononi A, Giorgi C, Marchi S, Missiroli S, Poletti F, Wieckowski MR, Pinton P. 2012. ATP synthesis and storage. Purinergic Signalling 8:343-357. DOI: 10.1007/s11302-012-9305-8. Lemasters JJ, Hackenbrock CR. 1978. [4] Firefly luciferase assay for ATP production by mitochondria. Methods in Enzymology. Vol 57. Academic Press, pp 36-50. Wibom R, Lundin A, Hultman E. 1990. A sensitive method for measuring ATP-formation in rat muscle mitochondria. Scandinavian Journal of Clinical and Laboratory Investigation 50:143-152. DOI: 10.1080/00365519009089146.  AOPWiki 2020-04-30T12:42:35

2021-06-14T13:40:17

Decrease, Cell proliferation

Cellular

Decreased cell proliferation describes the outcome of reduced cell division and cell growth. Cell proliferation is considered the main mechanism of tissue and organismal growth (Conlon 1999). Decreased cell proliferation has been associated with abnormal growth-factor signaling and cellular energy depletion (DeBerardinis 2008).

Multiple types of in vitro bioassays can be used to measure this key event: <ul> <li>ToxCast high-throughput screening bioassays such as “BSK_3C_Proliferation”, “BSK_CASM3C_Proliferation” and “BSK_SAg_Proliferation” can be used to measure cell proliferation status.</li> <li>Commercially available methods such as the well-established 5-bromo-2’-deoxyuridine (BrdU) (Raza 1985; Muir 1990) or 5-ethynyl-2’-deoxyuridine (EdU) assay. Both assays measure DNA synthesis in dividing cells to indicate proliferation status.</li> </ul>

Taxonomic applicability domain This key event is in general applicable to all eukaryotes, as most organisms are known to use cell proliferation to achieve growth.   Life stage applicability domain This key event is in general applicable to all life stages. As cell proliferation not only occurs in developing organisms, but also in adults.   Sex applicability domain This key event is sex-unspecific, as both genders use the same cell proliferation mechanisms.

CL:0000000

CL cell

High Unspecific

High

Embryo

High

Juvenile

High High High High

Conlon I, Raff M. 1999. Size control in animal development. Cell 96:235-244. DOI: 10.1016/s0092-8674(00)80563-2. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. 2008. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metabolism 7:11-20. DOI: <a href="https://doi.org/10.1016/j.cmet.2007.10.002">https://doi.org/10.1016/j.cmet.2007.10.002</a>. Muir D, Varon S, Manthorpe M. 1990. An enzyme-linked immunosorbent assay for bromodeoxyuridine incorporation using fixed microcultures. Analytical Biochemistry 185:377-382. DOI: <a href="https://doi.org/10.1016/0003-2697(90)90310-6">https://doi.org/10.1016/0003-2697(90)90310-6</a>. Raza A, Spiridonidis C, Ucar K, Mayers G, Bankert R, Preisler HD. 1985. Double labeling of S-phase murine cells with bromodeoxyuridine and a second DNA-specific probe. Cancer Research 45:2283-2287. AOPWiki 2020-11-12T17:57:08

2020-12-07T06:55:47

Decrease, Growth

Individual

Decreased growth refers to a reduction in size and/or weight of a tissue, organ or individual organism. Growth is normally controlled by growth factors and mainly achieved through cell proliferation (Conlon 1999).

Growth can be indicated by measuring weight, length, total volume, and/or total area of a tissue, organ or individual organism.

Taxonomic applicability domain This key event is in general applicable to all eukaryotes.   Life stage applicability domain This key event is applicable to early life stages such as embryo and juvenile.   Sex applicability domain This key event is sex-unspecific.

High Unspecific

High

Embryo

High

Juvenile

Moderate Moderate Moderate High High High Moderate

Conlon I, Raff M. 1999. Size control in animal development. Cell 96:235-244. DOI: 10.1016/s0092-8674(00)80563-2.  AOPWiki 2018-05-24T15:24:11

2022-07-06T07:36:50

<upstream-id>8784be18-7d27-45bd-912b-4a7aa5adc0cd</upstream-id> <downstream-id>ac939126-5a89-4f24-8852-fc95c7c77391</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9d98148> AOPWiki 2020-12-04T17:26:57

2020-12-04T17:26:57

<upstream-id>ac939126-5a89-4f24-8852-fc95c7c77391</upstream-id> <downstream-id>cab36f22-448f-45c0-b939-fceb80ef1b6a</downstream-id> This key event relationship describes reduced adenosine triphosphate (ATP) supply leading to reduced cell proliferation (cell growth, division or a combination of these).

The overall evidence supporting Relationship 2204 is considered moderate.

The biological plausibility of Relationship 2204 is considered high. Rationale: Cell proliferation is a well-known ATP-dependent process. Cell division processes, such as the mitotic cell cycle uses ATP for chromosome movements and DNA replication (Kingston 1999). The synthetic processes of major cellular components that are necessary for cell structure and growth, such as proteins and lipids, also require sufficient ATP supply (Bonora 2012). Depletion of ATP therefore has a negative impact on these processes.

The empirical support of Relationship 2204 is considered moderate. Evidence: <ul> <li>Incidence concordance: Exposure of human HeLa cells to 50 µM of the uncoupler CCCP for 1h led to 25% reduction in ATP, whereas a non-significant reduction in cell proliferation (Koczor 2009).</li> <li>Incidence concordance: Exposure of human RD cells to 20 µM of the uncoupler CCCP for 2h led to 20% ATP depletion, whereas a non-significant decrease in cell proliferation (Kuruvilla 2003).</li> <li>Incidence concordance: Exposure of human SE480 cells to 150 µM of the uncoupler flavanoid morin for 48h led to 35% ATP depletion and 35% reduction in cell proliferation (Sithara 2017).</li> </ul>

There are currently no inconsistencies based on the supporting literature.

The quantitative understanding of Relationship 2204 is moderate. Rationale: Quantitative relationships between total ATP and cell proliferation have been extensively investigated (Ahmann 1987; Crouch 1993). In general, a monotonic positive relationship can be assumed for the two events, albeit the actual quantitative relationship can vary across biological systems (e.g. cell types and species). It has also been suggested that a threshold of ATP depletion (85-90% compared to normal status) may exist to determine whether proliferation arrest (<85-90%) or cell death (>85-90%) will be triggered in mammals (Nieminen 1994).

High Unspecific

High

Embryo

High High

Taxonomic applicability Relationship 2204 is considered applicable to all eukaryotes, as ATP and cell proliferation are known to be tightly coupled in animals, plants and some microorganisms.   Sex applicability Relationship 2204 is considered applicable to all sexes, as ATP-dependent cell proliferation are used by both males and females in eukaryotes.   Life-stage applicability Relationship 2204 is considered applicable to all life stages, as ATP-dependent cell proliferation is an essential process for an organism throughout the entire life.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9e24c10> AOPWiki 2020-11-12T17:57:54

2020-12-07T07:43:07

<upstream-id>cab36f22-448f-45c0-b939-fceb80ef1b6a</upstream-id> <downstream-id>7aa6170c-56a0-4ace-8e04-d6d1e1501975</downstream-id> This key event relationship describes reduced cell proliferation (cell growth, division or a combination of these) leading to reduced tissue, organ or individual growth.

The overall evidence supporting Relationship 2205 is considered moderate.

The biological plausibility of Relationship 2205 is considered high. Rationale: The biological structural and functional relationship between cell proliferation and growth is well established. It is commonly accepted that the size of an organism, organ or tissue is dependent on the total number and volume of the cells it contains, and the amount of extracellular matrix and fluids (Conlon 1999). Impairment to cell proliferation can logically affect tissue and organismal growth.

The empirical support of Relationship 2205 is considered low. Rationale: Because cell proliferation is typically measured in vitro, while growth of an organism is measured in vivo, few studies have measured both in the same experiment. There is one zebrafish study reporting concordant relationship between reduced cell proliferation and embryo growth with some inconsistencies (Bestman 2015).

<ul> <li style="text-align:justify">In zebrafish embryos exposed to 2,4-DNP, significant growth inhibition (AO), as indicated by whole embryo length, caudal primary (CaP) motor neuron axons and otic vesicle length (OVL) ratio after 21h, somite width and eye diameter after 45h exposure was identified, after 21h,  whereas a non- significant reduction in cell proliferation was observed (Bestman 2015).</li> </ul>

The quantitative understanding of Relationship 2205 is moderate. Rationale: Multiple mathematical models describing the quantitative relationships between cell proliferation and tissue growth exist for both animals (Binder 2008) and plants (Mosca 2018). There are also numerous models that are specifically developed for predicting tumor growth based on the proliferation rate (Jarrett 2018).

High Unspecific

High

Embryo

High

Taxonomic applicability Relationship 2205 is considered applicable to all eukaryotes (both unicellular and multicellular), as growth (or population growth of alga) is well known to be achieved through cell proliferation in animals, plants and some microorganisms.   Sex applicability Relationship 2205 is considered applicable to both all sexes, as cell proliferation leading to growth is a fundamental process and not sex-specific.   Life-stage applicability Relationship 2205 is considered applicable to all life stages, as cell proliferation leading to growth is essential for maintaining basic biological processes throughout an organism’s life.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9eb3758> AOPWiki 2020-11-12T17:58:06

2022-07-06T07:43:26

Mitochondrial complex III antagonism leading to growth inhibition (1)

Agnes Aggy

You Song Norwegian Institute for Water Research (NIVA), Oslo, Norway

BY-SA

2.0

Growth is a regulatory relevant chronic toxicity endpoint for almost all organisms. Multiple OECD test guidelines have included growth either as a main endpoint of concern, or as an additional endpoint to be considered in the toxicity assessments. Relevant test guidelines include, but not only limited to:   -Test No. 201: Freshwater Alga and Cyanobacteria, Growth Inhibition Test -Test No. 208: Terrestrial Plant Test: Seedling Emergence and Seedling Growth Test -Test No. 211: Daphnia magna Reproduction Test -Test No. 212: Fish, Short-term Toxicity Test on Embryo and Sac-Fry Stages -Test No. 215: Fish, Juvenile Growth Test -Test No. 221: Lemna sp. Growth Inhibition Test -Test No. 228: Determination of Developmental Toxicity to Dipteran Dung Flies (Scathophaga stercoraria L. (Scathophagidae), Musca autumnalis De Geer (Muscidae)) -Test No. 241: The Larval Amphibian Growth and Development Assay (LAGDA) -Test No. 407: Repeated Dose 28-day Oral Toxicity Study in Rodents -Test No. 408: Repeated Dose 90-Day Oral Toxicity Study in Rodents -Test No. 416: Two-Generation Reproduction Toxicity -Test No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test -Test No. 443: Extended One-Generation Reproductive Toxicity Study -Test No. 453: Combined Chronic Toxicity/Carcinogenicity Studies

adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified adjacent

Not Specified

Juvenile

Not Specified

Adult

Not Specified Not Specified Not Specified

High

AOPWiki 2019-03-19T08:35:17

2023-09-25T16:26:59