Rotenone

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Rotenone
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Executive Summary Information

Compound
Toxicities Cytotoxicity
Mechanisms Rotenone is a competitive inhibitor of complex I of the electron transport chain. Its activity is specific to complex I, but the compound is nonselective with respect to cell type or species.
Comments Rotenone was selected as a mechanistic standard for inhibition of complex I in oxidative phosphorylation.
Feedback Contact Gold Compound Working Group (GCWG)
Rotenone
Rotenone.png
Identifiers
Leadscope Id LS-1830
CAS 83-79-4
Pathway DBs
Assay DBs
PubChem CID 6758
Omics DBs
Properties
pKa -4.57
ToxCast Accepted yes
Toxic Effect Apoptosis
ToxBank Accepted yes
Target complex I/ubiquinone
Toxicities Cytotoxicity


In Vivo Data ? Compound Assessment
Adverse Events ? Neurotoxicity

Rotenone is considered a model toxic of environmental Parkinson. After weeks of rotenone administration, a selective nigrostriatal dopaminergic degeneration develops that is similar to that observed in Parkinson disease. Electron microscopy revealed cytoplasmic inclusions in nigral neurons containing alphasynuclein and ubiquitin that are reminiscent of Lewy bodies . A brain rotenone concentration of 20–30 nM was reported enough to partially inhibit complex I, but too low to significantly impair respiration of brain mitochondria, produce ATP depletion and explain neurodegeneration. Parkinson's disease (PD) was positively associated with two groups of pesticides defined by mechanisms implicated experimentally—those that impair mitochondrial function and those that increase oxidative stress—supporting a role for these mechanisms in PD pathophysiology. In experimental models, rotenone, which inhibits mitochondrial complex I, induces loss of nigral dopaminergic neurons and behavioral changes associated with human PD.

Hepatotoxicity Rotenone is a powerful inhibitor of mitochondrial electron transport. The regulation of fatty acid synthesis in mitochondria by rotenone may be altered after chronic administration, resulting in fatty changes in the liver.

Cardiotoxicity Acute: Tachycardia, hypotension, impaired myocardial contractility (experimentally). Chronic: No data available

References:

-Tanner CM, et al. 2011. "Rotenone, Paraquat, and Parkinson’s Disease". Environ Health Perspect 119:866-872
-Henchcliffe C, Beal MF. 2008. "Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis". Nat Clin Pract Neurol 4(11):600–609
-International Programme on Chemical Safety

Toxicity Mechanisms ? Rotenone is known to be a potent inhibitor of complex I of the mitochondrial respiratory chain in all cell types, by inhibiting the function of mitochondrial NADPH dehydrogenase activity, therefore leading to a decrease in aerobic metabolism and development of a lactic acidosis. This inhibition of the mitochondrial respiratory chain leads to an increase in the production of hydrogen peroxide, and superoxide and oxygen radical species. It is thought that the production of these oxidant species is the mechanism by which rotenone exerts its acute toxic effects, leading to fragmentation of DNA and lipid peroxidation increased lactate dehydrogenase release and an increase protein carbonyl concentration, which is a marker of apoptotic cell death.

Rotenone induces apoptosis; the specifics of the mechanism for this induction have not been defined. Mitochondrial dysfunction, in particular the induction of the mitochondrial membrane permeability transition, has been implicated.

Assays with HL-60 (promyelocitic leukemia) and BJAB (B-cell lymphoma) cultured human cells at 5 uM rotenone induce apoptosis with changes in mitochondrial membrane potential, caspase-3 activation, and DNA ladder formation, and these apoptotic events are secondary to H2O2 production and mitochondrial dysfunction

References:

-D M Wood et al., "Fatality after deliberate ingestion of the pesticide rotenone: a case report" Crit Care. 2005; 9(3): R280–R284.
-Carmen Gomez et al. " Pesticides and impairment of mitochondrial function in relation with the parkinsonian syndrome" Frontiers in Bioscience 12, 1079-1093, January 1, 2007
-International Programme on Chemical Safety
-Isenberg JS et al., "Role of the mitochondrial membrane permeability transition (MPT) in rotenone-induced apoptosis in liver cells". Toxicol Sci. 2000 Feb;53 (2):340-51.

Therapeutic Target ? Used as a broad-spectrum insecticide, piscicide, and pesticide, it occurs naturally in the roots and stems of several plants.

PubMed references

The following resource link will perform a PubMed query for the terms "Rotenone" and "liver toxicity".
Rotenone Search

EPA Summary

EPA Summary

The table listed below contains a summarized listing of toxic effect information leveraged from the 6th European Framework Programme project LIINTOP. For a complete listing of the Gold Compound evaluation criteria please see the Gold Compound Evaluation and Comments immediately following the summary table below.

SMILES c12c3c(O[C@H](C3)C(C)=C)ccc1C([C@H]1c3c(cc(OC)c(c3)OC)OC[C@@H]1O2)=O
InChI

InChI=1S/C23H22O6/c1-11(2)16-8-14-15(28-16)6-5-12-22(24)21-13-7-18(25-3)19(26-4)9-17(13)27-10-20(21)29-23(12)14/h5-7,9,16,20-21H,1,8,10H2,2-4H3/t16-,20-,21+/m1/s1

InChI-Key

JUVIOZPCNVVQFO-HBGVWJBISA-N

Supplier Sigma Aldrich
Summary Hepatotoxic Effects from the LIINTOP FP6 Program
Hepatocellular necrosis.gif Apoptosis.gif Transporter inhibition.gif Cholestatic.gif Steatotic.gif Phospholipidosis.gif Hepatocyte function.gif Mithochondria impairment.gif Oxidative stress.gif DNA synthesis genotoxicity.gif Covalent binding.gif Idiosyncrasia metabolic.gif Idiosyncrasia immune.gif Bioactivation required.gif LIINTOP severity.gif References
+ +

[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]

References

  1. ↑ Hynes, J., Marroquin, L.D., Ogurtsov, V.I., Christiansen, K.N., Stevens, G.J., Papkovsky, D.B., Will, Y., 2006. Investigation of drug-induced mitochondrial toxicity using fluorescence-based oxygen-sensitive probes. Toxicol. Sci. 92, 186–200.
  2. ↑ Labbe, G., Pessayre, D., Fromenty, B., 2008. Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam. Clin. Pharmacol. 22, 335–353.
  3. ↑ Masubuchi, Y., 2006. Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab. Pharmacokinet. 21, 347–356.
  4. ↑ Feldmann, G., 2006. Liver apoptosis. Gastroenterol. Clin. Biol. 30, 533–545.
  5. ↑ Gomez-Lechon, M.J., O’Connor, E., Castell, J.V., Jover, R., 2002. Sensitive markers used to identify compounds that trigger apoptosis in cultured hepatocytes. Toxicol. Sci. 65, 299–308.
  6. ↑ Gomez-Lechon, M.J., O’Connor, J.E., Lahoz, A., Castell, J.V., Donato, M.T., 2008. Identification of apoptotic drugs: multiparametric evaluation in cultured hepatocytes. Curr. Med. Chem. 15, 2071–2085.
  7. ↑ Gomez-Lechon, M.J., Ponsoda, X., O’Connor, E., Donato, T., Jover, R., Castell, J.V., 2003. Diclofenac induces apoptosis in hepatocytes. Toxicol. in Vitro 17, 675– 680.
  8. ↑ Kass, G.E., Macanas-Pirard, P., Lee, P.C., Hinton, R.H., 2003. The role of apoptosis in acetaminophen-induced injury. Ann. NY Acad. Sci. 1010, 557–559.
  9. ↑ Hynes, J., Marroquin, L.D., Ogurtsov, V.I., Christiansen, K.N., Stevens, G.J., Papkovsky, D.B., Will, Y., 2006. Investigation of drug-induced mitochondrial toxicity using fluorescence-based oxygen-sensitive probes. Toxicol. Sci. 92, 186–200.
  10. ↑ Johannsen, D.L., Ravussin, E., 2009. The role of mitochondria in health and disease. Curr. Opin. Pharmacol. 9, 780–786.
  11. ↑ Jones, D.P., Lemasters, J.J., Han, D., Boelsterli, U.A., Kaplowitz, N., 2010. Mechanisms of pathogenesis in drug hepatotoxicity putting the stress on mitochondria. Mol. Interv. 10, 98–111.
  12. ↑ Labbe, G., Pessayre, D., Fromenty, B., 2008. Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam. Clin. Pharmacol. 22, 335–353.
  13. ↑ Masubuchi, Y., 2006. Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab. Pharmacokinet. 21, 347–356.


PK-ADME ? Compound Assessment
PK parameters ? Gastrointestinal absorption is low and incomplete. In animals, rotenone is hundreds of times more toxic intravenously than orally. Fats and oils increase absorption. Data on pulmonary or dermal absorption are not available. No data are available concerning biological half-life or distribution after oral ingestion, inhalation, or dermal exposure.

In the mouse and rat, approximately 20% of a dose is recovered in urine within 24 hours of oral administration

It is highly lipophilic and easily crosses the blood-brain barrier. It does not depend on the dopamine transporter for access to cell, causing an uniform complex I inhibition throughout the brain

References:

-Carmen Gomez et al. " Pesticides and impairment of mitochondrial function in relation with the parkinsonian syndrome" Frontiers in Bioscience 12, 1079-1093, January 1, 2007
-International Programme on Chemical Safety

Therapeutic window ? Human mean lethal oral dose is estimated from 0.3 to 0.5 g/kg.

The lethal dose in mammals ranges from 0.05 to 3000 g/kg

References:

-International Programme on Chemical Safety

LD 50 rat oral: 0,33 mmol/kg or 130,2 mg/kg.

References:

-"Guidance Document on Using In Vitro Data to Estimate In Vivo Starting Doses for Acute Toxicity" August 2001 NIH Publication No. 01-4500

Metabolically activated ? Rotenone is metabolized by the liver. After intravenous injection in the rat and mouse, rotenone is metabolized by hepatic microsomal enzymes. Several metabolites have been identified as rotenoids (rotenolone I and II, hydroxyl- and dihydroxyrotenones, etc.) with toxicity similar to rotenone. One mechanism of metabolism was demethylation.

References:

-International Programme on Chemical Safety

Omics and IC50 Data ? Compound Assessment
Gene expression profiles known. ? References:
-James G. Greene et al., "Neuron-selective changes in RNA transcripts related to energy metabolism in toxic models of parkinsonism in rodents" Neurobiology of Disease 38 (2010) 476–481
-F. Ishikawa et al., "Gene Expression Profiling Identifies a Role for CHOP During Inhibition of the Mitochondrial Respiratory Chain" J Biochem (2009) 146 (1): 123-132.
-Elizabeth L. MacKenzie et al., "role and regulation of ferritin h in rotenone-mediated mitochondrial oxidative stress" Free Radic Biol Med. 2008 May 1; 44(9): 1762–1771.
Proteomics profiles known. ? References:
-K. Hanisch et al., "Proteomic Signatures of the Zebrafish (Danio rerio) Embryo: Sensitivity and Specificity in Toxicity Assessment of Chemicals" International Journal of Proteomics, Volume 2010 (2010), Article ID 630134, 13 pages
-Jin J. et al., "Identification of novel proteins affected by rotenone in mitochondria of dopaminergic cells." BMC Neurosci. 2007 Aug 16;8:67.
Metabonomics profiles known. ?
Fluxomics profiles known. ?
Epigenomics profiles known. ?
Observed IC50 for in vitro cellular efficacy. ?
Observed IC50 for in vitro cellular toxicity studies. ? It inhibits the oxidation of NADH to NAD at complex I and thereby blocks the utilization of glutamate, alpha-ketoglutarate, and pyruvate in energy metabolism via blockage of the tricarboxylic acid cycle.
  • Bovine heart mitochondrial function: IC50 = 0.1-0.2 nmol/ mg protein
  • In isolated beef heart or liver mitochondria, the median IC50 is 0.07 nmol/mg of protein with a Ki of 4 nM
  • The IC50 of rotenone for complex I inhibition was in the range 1.7- 2.2 uM.
  • In isolated rat liver mitochondria, the aerobic oxidation of pyruvate is almost completely inhibited by rotenone.

References:

-Carmen Gomez et al. " Pesticides and impairment of mitochondrial function in relation with the parkinsonian syndrome" Frontiers in Bioscience 12, 1079-1093, January 1, 2007
-International Programme on Chemical Safety

Mouse fibroblast cell line BALB/c 3T3 A31,human NHK cells Cytotoxicity IC 50: 0.00013 LD 50 rat oral: 0,33 mmol/kg or 130,2 mg/kg

References:

-"Guidance Document on Using In Vitro Data to Estimate In Vivo Starting Doses for Acute Toxicity" August 2001 NIH Publication No. 01-4500

Physical Properties ? Compound Assessment
Accepted and listed within the ToxCast/Tox21 program. ? Yes - Included in ToxCast Phase I and II Chemicals List
Substance stability. ? Air and light sensitive Sigma Aldrich 45656 Product details

Decomposes rapidly in organic solvents exposed to light and air Rotenone EPA Pesticide Fact Sheet 10/88

Soluble in buffer solution at 30 times the in vitro IC50 for toxicity. ? Water: 0.0002 mg/ml Rotenone EPA Pesticide Fact Sheet 10/88


estimated intrinsic solubility : 1.8903e-4 mg/ml
estimated solubility in pure water at pH 7: 1.8903e-4 mg/ml
estimated solubility in water at pH 7.4: 1.89e-4 mg/ml (Calculations performed using ACD/PhysChem v 12.0)

Solubility in DMSO 100 times buffer solubility. ? Soluble to 100 mM in DMSO Tocris Bioscience 3616 Product details
Vessel binding properties. ? Unknown
Vapor pressure. (Non-volatile) ? Estimated vapor pressure (25°C): 6.94E-010 mmHg (Calculation performed using EPI Suite v4.1)

Calculated/Predicted Properties

Water Solubility Results
pH Sol,mg/ml 0 Graph
2 2.71E-4 100 Rotenone solubility.png
5.5 2.71E-4 100
6.5 2.71E-4 100
7.4 2.71E-4 100
10 2.71E-4 100
Summary Solubility Data
Intrinsic Solubility,mg/ml 2.7059E-4
Intrinsic Solubility,log(S,mol/l) -6.1636
Solubility in Pure Water at pH = 7,mg/ml 2.7059E-4
Calculations performed using ACD/PhysChem v 9.14
LogD Results
pH LogD Graph
2 4.65 Rotenone logd.png
5.5 4.65
6.5 4.65
7.4 4.65
10 4.65
Calculations performed using ACD/PhysChem v 9.14
Single-valued Properties
Property Value Units Error
LogP 4.65 0.44
MW 394.42 -
PSA 63.22 -
FRB 3 -
HDonors 0 -
HAcceptors 6 -
Rule Of 5 0 -
Molar Refractivity 104.93 cm3 0.3
Molar Volume 310.3 cm3 3
Parachor 805.17 cm3 6
Index of Refraction 1.59 0.02
Surface Tension 45.33 dyne/cm 3
Density 1.27 g/cm3 0.06
Polarizability 41.6 10E-24 cm3 0.5
Calculations performed using ACD/PhysChem v 9.14
Property Name Value Units Source
pKa -4.57 SPARC v4.5
Estimated VP 6.94E-10 mm Hg EPI Suite v4.10
Estimated VP 9.25E-08 Pa EPI Suite v4.10
Estimated Water Solubility 1.045 mg/L EPI Suite v4.10
WATERNT Frag Water Solubility Estimate 0.013116 mg/L EPI Suite v4.10
pKa Results
Acidic/Basic Acidic/Basic Aparrent pKa Value Error
A = Acidic
B = Basic
MA = Most Acidic
MB = Most Basic
Calculations performed using ACD/PhysChem v 9.14

Authors of this ToxBank wiki page

David Bower, Egon Willighagen, Matthew Clark
Retrieved from "http://wiki.toxbank.net/wiki/Rotenone"
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