Allyl alcohol

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Executive Summary Information

Compound Allyl alcohol
Toxicities Cytotoxicity with fibrosis
Mechanisms Allyl alcohol is oxidized to acrolein by alcohol dehydrogenase, primarily in the liver. Acrolein is a potent alkylating reagent that is selective for glutathione and protein cysteines.
Comments Allyl alcohol was selected as a compound with a relatively well-defined alkylating MOA that causes fibrosis. SAFETY CAUTION: allyl alcohol is a lachrymator, is readily absorbed through the skin, and can cause chemical burns to exposed organs, including eyes, lungs, and skin.
Feedback Contact Gold Compound Working Group (GCWG)
Allyl alcohol
Allylalcohol.png
Identifiers
Leadscope Id LS-433
CAS 107-18-6
ChemSpider 13872989
ChEBI 16605
Pathway DBs
KEGG C02001
Assay DBs
PubChem CID 7858
ChEMBL 234926
Omics DBs
Open TG-Gate 00010
Properties
ToxCast Accepted no
ToxBank Accepted yes
Approved on 2012-05-01
Toxicities Cytotoxicity,Fibrosis



In Vivo Data ? Compound Assessment
Adverse Events ? Repetitive intraperitoneal injection of allyl alcohol induces hepatic fibrosis in rats, and allyl alcohol is a reference standard for liver fibrosis.

Allyl alcohol is highly toxic to rat liver, producing extensive periportal injury in intact animals and cellular necrosis in isolated hepatocytes. Its toxicity appears to be exclusively mediated by its oxidation product, acrolein. The preferential occurrence of allyl alcohol injury in zone 1 hepatocytes is due to this oxygen-dependent bioactivation.

In mice, acrolein induces selective myofilament impairment, which may be related to the modification of proteins involved in myocardial contraction and energy metabolism; neuronal damage, also mediated by protein adduct formation; increased circulating levels of cholesterol and triglycerides; and lung and bladder cancer due to induction of DNA damage along with inhibition of DNA repair. Cancer is also observed in humans, and cardiotoxicity was identified as the cause of death in a case of fatal human allyl alcohol intoxication.

References:

-Wikipedia
-ToxNet/HSDB
-SA. Jung et al. "Experimental model of hepatic fibrosis following repeated periportal necrosis induced by allyl alcohol". Scand J Gastroenterol. 2000 Sep;35(9):969-75.
-Daniel J. Conklin et al. " Acrolein-induced dyslipidemia and acute-phase response are independent of HMG-CoA reductase" Mol. Nutr. Food Res. 2011, 55, 1411–1422
-Moon-shong Tang et al. "Acrolein induced DNA damage, mutagenicity and effect on DNA repair" Mol. Nutr. Food Res. 2011, 55, 1291–1300
-Luo J. et al. " Mechanisms of acrolein-induced myocardial dysfunction: implications for environmental and endogenous aldehyde exposure." Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3673-84
-RM. LoPachin " Molecular Mechanisms of the Conjugated α,β-unsaturated Carbonyl Derivatives: Relevance to Neurotoxicity and Neurodegenerative Diseases" Toxicological Sciences 104(2), 235–249 (2008)
-JP Kehrer "The Molecular Effects of Acrolein" Toxicol. Sciences 57, 6-15 (2000)
-Stefan W. Toennes*, Karl Schmidt, Anabel S. Fandiño, and Gerold F. Kauert, “A Fatal Human Intoxication with the Herbicide Allyl Alcohol (2-Propen-1-ol)”, J Anal Toxicol (2002) 26 : 55-57.

Toxicity Mechanisms ? Allyl alcohol hepatotoxicity is mediated by its oxidation to acrolein, catalyzed by alcohol dehydrogenase. This highly reactive α,β- unsaturated aldehyde readily alkylates model proteins in vitro. Acrolein is selective for sulfhydryl groups, including glutathione; and alkylation of proteins is assumed to be the event actually leading to cell injury. Acrolein also alkylates nitrogen nucleophiles, primarily lysine and deoxyguanosine, at lower rates than thiols.

Allyl alcohol toxicity is accompanied by oxidative stress, collapse of mitochondrial membrane potential, and lipid peroxidation. However, cells are committed to cell death, presumably via irreversible protein alkylation, before these markers of toxicity are observed. Although GSH is extensively alkylated, cytotoxicity is more correlated with protein alkylation than with alkylation of GSH. Depletion of ATP is also observed, but cells are irreversibly committed to cell death before ATP depletion is significant. In this regard, allyl alcohol is a reducing agent and differs from many other alkylating toxicants in that NAD(P)H levels and the cellular reduction potential increase in the initial stages of exposure. The NAD(P)H thus formed can be a source of ATP even though ATP formation via oxidation of glucose may be shut down by protein alkylation. In contrast, iodoacetamide, which does not require activation, blocks ATP and NADH formation concomitantly because it blocks entry into glycolysis, and extensive loss of ATP is observed before release of LDH commences. Thus, allyl alcohol is distinguished from other alkylating agents in that protein alkylation can occur during a time period when the energy charge and reducing potential of the cell are preserved. This fundamental difference may be a clue in beginning to understand why allyl alcohol causes fibrosis while another alkylating agent, acetaminophen, does not.

Modulation of intra- and extra-cellular signaling pathways by acrolein has been demonstrated and is presumably related to the pro-fibrotic activity of acrolein. Acrolein inhibits activation of the transcription factor NF-kB; and activation of protein kinase Cδ (PKCδ) by allyl alcohol is associated with its cytotoxicity to hepatocytes. Sensitivity of liver to allyl alcohol is increased by inflammation, and LPS enhances allyl alcohol-induced toxicity. However the quantitatively dominant signals that mediate fibrosis are not fully understood.

References:

-K. Alam et al. "Beneficial Effect of Nitric Oxide Synthase Inhibitor on Hepatotoxicity Induced by Allyl Alcohol" J. Biochem Molecular Toxicology Volume 15, Number 6, 2001
-Scott S. Auerbach et al. "A Comparative 90 Day Toxicity Study of Allyl Acetate, Allyl Alcohol and Acrolein" Toxicology. 2008 November 20; 253(1-3): 79–88.
-ToxNet/HSDB
-P. C. Burcham and F. Fontaine "Extensive Protein Carbonylation Precedes Acrolein-Mediated Cell Death in Mouse Hepatocytes" J. Biochem Molecular Toxicology Volume 15, Number 6, 2001
-J.F. Maddox et al. "Allyl alcohol activation of protein kinase c δ leads to cytotoxicity of rat hepatocytes". (2003) Chem. Res. Toxicol. 16, 609–615
-J.F. Maddox et al. "15-Deoxy Prostaglandin J2 Enhances Allyl Alcohol–Induced Toxicity in Rat Hepatocytes" Toxicol. Sci. (2004) 77 (2): 290-298.
-Lora E. Rikans, David Y. Cai, K. Roger Hornbook, “Loss of mitochondrial membrane potential is not essential to hepatocyte killing by ally1 alcohol”, Toxicology Letters 81 (1995) 159-165.
-Lora E. Rikans, David Y. Cai, K. Roger Hornbook, “Oxidation of pyridine nucleotides is an early event in the lethality of allyl alcohol”, Toxicology 106 (1996) 85-92.
-Lora E. Rikans, David Y. Cai, K. Roger Hornbook, “Allyl alcohol cytotoxicity in isolated rat hepatocytes: effects of azide, fasting, and fructose”, J Toxicol Environ Health. (1995) 44:1-11.

Therapeutic Target ? Allyl alcohol is not used therapeutically.

Human Adverse Events

The following data table has been mined from the Adverse Events Reporting System (AERS) of the US FDA. Significant human liver events. The first column ("# Reports") is the number of reports found for the corresponding adverse event reported in the third column ("Adverse Event"). The second column ("Report:Baseline Ratio") is ratio calculated from the number of reports ("# Reports") divided by a calculated expected statistical baseline number of reports.

# Reports Report:Baseline Ratio Adverse Event
2 4.75867 adenoviral hepatitis
1 8.64492 bile duct necrosis
1 9.09991 biliary fistula
1 6.56576 hepatitis infectious
27 9.73229 venoocclusive liver disease

PubMed references

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

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 O=C(OC)[C@]4(c2c(c1ccccc1n2)CCN3C[C@](O)(CC)C[C@@H](C3)C4)c5c(OC)cc6c(c5)[C@@]89[C@@H](N6C=O)[C@@](O)(C(=O)OC)[C@H](OC(=O)C)[C@@]7(/C=C\CN([C@@H]78)CC9)CC
InChI

InChI=1S/C46H56N4O10/c1-7-42(55)22-28-23-45(40(53)58-5,36-30(14-18-48(24-28)25-42)29-12-9-10-13-33(29)47-36)32-20-31-34(21-35(32)57-4)50(26-51)38-44(31)16-19-49-17-11-15-43(8-2,37(44)49)39(60-27(3)52)46(38,56)41(54)59-6/h9-13,15,20-21,26,28,37-39,47,55-56H,7-8,14,16-19,22-25H2,1-6H3/t28-,37+,38-,39-,42+,43-,44-,45+,46+/m1/s1

InChI-Key

OGWKCGZFUXNPDA-XQKSVPLYSA-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]

References

  1. Feldmann, G., 2006. Liver apoptosis. Gastroenterol. Clin. Biol. 30, 533–545.
  2. 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.
  3. 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.
  4. 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.
  5. 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.

PK-ADME ? Compound Assessment
PK parameters ?
Therapeutic window ? Oral Reference Dose (RfD): 0.005 mg/kg/day for impaired renal function and increased liver and kidney weights.

Threshold limit value in air: 2 ppm (eye irritation) Human exposure standard: 20 ppm is considered dangerous to life.

References:

-ToxNet/IRIS
-Pubchem

Metabolically activated ? Allyl alcohol is oxidized to acrolein by alcohol dehydrogenase. Data strongly support the role of acrolein as the primary reactive species and toxicant following allyl alcohol exposure. Acrolein is a highly reactive, α,β-unsaturated aldehyde, which is a powerful electrophile and reacts with nucleophiles. Of the common cellular nucleophiles, acrolein is selective for sulfhydryl groups.

Acrolein can subsequently be detoxified by aldehyde dehydrogenase to acrylic acid, which is a less reactive thiol reagent, or by conjugation to glutathione and excretion. Degradation products of glutathione adducts, S-(3-hydroxypropyl) mercapturic acid and S-(2-carboxyethyl) mercapturic acid, are found in the urine of rats.

Acrolein can be epoxidized by cytochromes P450 to the hard electrophile and known mutagen/carcinogen, glycidaldehyde.

References:

- K. Alam et al. "Beneficial Effect of Nitric Oxide Synthase Inhibitor on Hepatotoxicity Induced by Allyl Alcohol" J. Biochem Molecular Toxicology Volume 15, Number 6, 2001
- Scott S. Auerbach et al. "A Comparative 90 Day Toxicity Study of Allyl Acetate, Allyl Alcohol and Acrolein" Toxicology. 2008 November 20; 253(1-3): 79–88.
-Patel JM, Wood JC, Leibman KC, “The biotransformation of allyl alcohol and acrolein in rat liver and lung preparations”, Drug Metab Dispos. 1980; 8(5):305-8.

Omics and IC50 Data ? Compound Assessment
Gene expression profiles known. ?

References:

-Jeffrey F. Waring et al. " Microarray analysis of hepatotoxins in vitro reveals a correlation between gene expression profiles and mechanisms of toxicity" Toxicology Letters 120 (2001) 359–368 (rat hepatocytes were treated with 15 known hepatoxins (amongst them allyl alcohol) and microarray technology was used to characterize the compounds based on gene expression changes)
-Daniel J. Conklin et al., "Acrolein-induced dyslipidemia and acute-phase response are independent of HMG-CoA reductase" Mol. Nutr. Food Res. 2011, 55, 1411–1422 (Changes in hepatic gene expression were examined)

Proteomics profiles known. ?

References:

-PC. Spiess " Proteomic profiling of acrolein adducts in human lung epithelial cells" Journal of Proteomics Vol 74, Issue 11, 19 October 2011, Pag 2380–2394
-JD. Chavez " Site-specific proteomic analysis of lipoxidation adducts in cardiac mitochondria reveals chemical diversity of 2-alkenal adduction" Journal of Proteomics Vol 74, Issue 11, 19 October 2011, Pag 2417–2429

Metabonomics profiles known. ?
Fluxomics profiles known. ?
Epigenomics profiles known. ?
Observed IC50 for in vitro cellular efficacy. ? NA
Observed IC50 for in vitro cellular toxicity studies. ? IC50 = 50 µM for mouse hepatocytes. There is marked time dependence to increases in LDH leakage that approaches a plateau within 60 min. The dose response curve is very steep with no LDH release at 25 uM and 70 and 90% LDH leakage within 60 min at 100 and 200 µM, respectively.

IC50 = 50-75 uM for cytotoxicity in rat hepatocytes at 90 min.

When rat hepatocytes were incubated with 500 uM allyl alcohol, cellular NAD(P)H increased over the first 30 min due to oxidation of allyl alcohol. Administration of DTT at 30 min protected against progression to cell death, presumably by trapping excess acrolein as GSH began to be depleted. DTT administered at 60 min did not rescue cells from cell death, and oxidation of NAD(P)H occurred in the period between 60 and 90 min, presumably as glycolysis and other sources of reducing power were shut down. Release of LDH was beginning to be observed by 90 min. Loss of ATP and mitochondrial membrane potential were also beginning to occur by 60 min but were determined to be a result of the events that were causing cell death and not a direct cause of cell death in themselves.


References:

- P. C. Burcham and F. Fontaine, "Extensive Protein Carbonylation Precedes Acrolein-Mediated Cell Death in Mouse Hepatocytes" J. Biochem Molecular Toxicology Volume 15, Number 6, 2001
-Jane F. Maddox, Alison C. Domzalski, Robert A. Roth, and Patricia E. Ganey, “15-Deoxy Prostaglandin J2 Enhances Allyl Alcohol–Induced Toxicity in Rat Hepatocytes”, Toxicological Sciences 77, 290–298 (2004).
-Lora E. Rikans, David Y. Cai, K. Roger Hornbook, “Loss of mitochondrial membrane potential is not essential to hepatocyte killing by ally1 alcohol”, Toxicology Letters 81 (1995) 159-165.
-Lora E. Rikans, David Y. Cai, K. Roger Hornbook, “Oxidation of pyridine nucleotides is an early event in the lethality of allyl alcohol”, Toxicology 106 (1996) 85-92.
-Lora E. Rikans, David Y. Cai, K. Roger Hornbook, “Allyl alcohol cytotoxicity in isolated rat hepatocytes: effects of azide, fasting, and fructose”, J Toxicol Environ Health. (1995) 44:1-11.

Physical Properties ? Compound Assessment
Accepted and listed within the ToxCast/Tox21 program. ? No - Not included in ToxCast Phase I and II Chemicals List
Substance stability. ? Stable under normal handling conditions but unstable to oxidizing agents and strong acid.
Soluble in buffer solution at 30 times the in vitro IC50 for toxicity. ? 32 g/100 ml

References:

-Chemical Land 21


estimated intrinsic solubility: 124 mg/ml
estimated solubility in pure water at pH 6.87: 124 mg/ml
estimated solubility in water at pH 7.4: 124 mg/ml
Calculations performed using ACD/PhysChem v 12.0

Solubility in DMSO 100 times buffer solubility. ? Stock solutions may be prepared in water or buffer.
Vessel binding properties. ?
Vapor pressure. (Non-volatile) ? Vapor pressure: 23.8 mmHg (25°C) Sigma Aldrich (240532) Product details

Estimated vapor pressure (25°C): 23.4 mmHg (Calculation performed using EPI Suite v4.1)

Calculated/Predicted Properties

Water Solubility Results
pH Sol,mg/ml Flags  % Graph
2 54.05 B 100 Vincristine solubility.png
5.5 1.72 B 100
6.5 9.91E-2 BN 96/4
7.4 1.51E-2 BN 72/28
10 4.63E-3 AN 6/93
Summary Solubility Data
Intrinsic Solubility,mg/ml 4.3026E-3
Intrinsic Solubility,log(S,mol/l) -5.2827
Solubility in Pure Water at pH = 8.26,mg/ml 5.7934E-3
Calculations performed using ACD/PhysChem v 9.14
Single-valued Properties
Property Value Units Error
Molar Refractivity 221.09 cm3 0.4
Molar Volume 586.86 cm3 5
Parachor 1721.57 cm3 6
Index of Refraction 1.68 3.33E-2
Surface Tension 74.06 dyne/cm 5
Density 1.41 g/cm3 0.1
Polarizability 87.65 10E-24 cm3 0.5
Calculations performed using ACD/PhysChem v 9.14
Property Name Value Units Source
pKa - SPARC v4.5
Estimated VP 4.78E-29 mm Hg EPI Suite v4.10
Estimated VP 6.37E-27 Pa EPI Suite v4.10
Estimated Water Solubility 0.1152 mg/L EPI Suite v4.10
WATERNT Frag Water Solubility Estimate 0.4825 mg/L EPI Suite v4.10
pKa Results
Acidic/Basic Acidic/Basic Aparrent pKa Value Error
40 A 16.7 0.6
59 A 14.61 0.4
18 MA 11.1 0.6
53 MB 7.9 0.6
7 B 5.54 0.7
40 B -2.95 0.6
9 B -4.58 0.7
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
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