predicting indirect dna damage by simulating metabolic activation of chemicals
DESCRIPTION
Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals. Ovanes Mekenyan, Milen Todorov, Ksenia Gerova. Laboratory of Mathematical Chemistry, Bulgaria. 2 nd McKim Workshop on Reducing Data Redundancy in Cancer Assessment Baltimore, 8-10 May 2012. Outlook Goal Methods - PowerPoint PPT PresentationTRANSCRIPT
![Page 1: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/1.jpg)
Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals
1
2nd McKim Workshop on Reducing Data Redundancy in Cancer AssessmentBaltimore, 8-10 May 2012
Ovanes Mekenyan, Milen Todorov, Ksenia Gerova
Laboratory of Mathematical Chemistry, Bulgaria
![Page 2: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/2.jpg)
2
Outlook
• Goal• Methods• Data• Predicting:
• AMES mutagenicity without metabolic activation• AMES metabolic activation chemicals negative as parents• Illustrating metabolic activation • False positives after metabolic activation• False negatives after metabolic activation
• Conclusions
![Page 3: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/3.jpg)
3
Outlook
• Goal• Methods• Data• Predicting:
• AMES mutagenicity without metabolic activation• AMES metabolic activation chemicals negative as parents• Illustrating metabolic activation • False positives after metabolic activation• False negatives after metabolic activation
• Conclusions
![Page 4: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/4.jpg)
4
• Predicting indirect DNA damage in the General Workflow Diagram for screening large chemicals inventories for carcinogenicity
Goal
![Page 5: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/5.jpg)
5
General Flow Diagram for Screening Large Inventories for carcinogenicity
Inventory
Direct DNA Reactive
Chemicals
DNA reactiveMetabolites
Ames Positive with S9
Ames Positive w/o S9
Classify asGenotoxic Bacterial Mutagen
High Carcinogenicity
Potential?
Generate metabolites
YY
Receptor-Based Screening
Low Carcinogenit
Potential
Y
N
Y Y
Protein Reactive
Chemicals
High Priority for Tumor
Promotion Assays
No-ThresholdRisk Assessment
CTA Assays for Nongenotoxic/
EpigeneticChemicals
Intermediate Priority for
Tumor Promotion
AssaysThreshold EffectRisk Assessment
![Page 6: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/6.jpg)
6
General Flow Diagram for Screening Large Inventories for carcinogenicity
Inventory
Direct DNA reactive
Indirect DNA reactive
Ames Positive with S9
Ames Positive w/o S9
Bacterial Mutagen
Chrom Ab ?MicroNucl ?
Protein OASIS
Generate metabolites
N
Y
Y
Receptor-Based Epigenetic
Screen
Low Carcinogenit
Potential
Y
Chrom Ab ?MicroNucl ?
Refine TIMES/Structural alerts
N
YY
N
Oxidative stress?
In vivo Mammal Tests
Protein Reactive
Return for further screening
![Page 7: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/7.jpg)
7
Outlook
• Goal• Methods• Data• Predicting:
• AMES mutagenicity without metabolic activation• AMES metabolic activation chemicals negative as parents• Illustrating metabolic activation • False positives after metabolic activation• False negatives after metabolic activation
• Conclusions
![Page 8: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/8.jpg)
DNA binding profile by OASIS
DNA binding profile by OECD
8
Methods:
• QSAR Toolbox profiles for DNA binding
![Page 9: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/9.jpg)
Illustration of the DNA binding profile of the QSAR Toolbox
9
![Page 10: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/10.jpg)
![Page 11: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/11.jpg)
Known DNA (covalent) binding mechanisms
![Page 12: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/12.jpg)
Known DNA (covalent) binding mechanisms
![Page 13: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/13.jpg)
Structural boundaries of the category
![Page 14: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/14.jpg)
Structural boundaries of the category
![Page 15: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/15.jpg)
DNA binding profile by OASIS
DNA binding profile by OECD
25
Methods:
• QSAR Toolbox profiles for DNA binding
• TIMES Metabolic simulator for rat liver S9
![Page 16: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/16.jpg)
OASIS Metabolic Simulator
• Prioritized list of non-enzymatic (abiotic) and enzymatic molecular transformations;
• Molecular transformations are characterized by:
Source and product fragments;Inhibiting “masks” preventing the
application of metabolic reactions if necessary;
• Substructure-matching software engine applies the simulated biochemical
• Reproduces the documented metabolic pathways and toxicity endpoint resulting from metabolic activation of chemicals
26
![Page 17: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/17.jpg)
Illustration the OASIS Metabolic Simulators
(extract from the Rat in vivo metabolism simulator)
27
![Page 18: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/18.jpg)
28
Substrate Principle transformations MetabolitesSimulator of metabolismSimulator of metabolism
Aliphatic C-oxidation
C CH3 C CH2OH
Epoxidation
C C C C
O
Aliphatic C-oxidation
C CH2OH C C
O
H
Epoxide Hydration
C C
O
C C OHHO
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
![Page 19: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/19.jpg)
29
Substrate Principle transformations MetabolitesSimulator of metabolismSimulator of metabolism
Aliphatic C-oxidation
C CH3 C CH2OH
Epoxidation
C C C C
O
Aliphatic C-oxidation
C CH2OH C C
O
H
Epoxide Hydration
C C
O
C C OHHO
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
P= 0.90
P= 0.93
P= 0.94
P= 0.95
P= 0.96
P= 0.97
![Page 20: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/20.jpg)
30
Substrate Principle transformations Metabolites
Aliphatic C-oxidation
C CH3 C CH2OH
Epoxidation
C C C C
O
Aliphatic C-oxidation
C CH2OH C C
O
H
Epoxide Hydration
C C
O
C C OHHO
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
P= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
CH2C CH3
- Isopropenylbenzene
![Page 21: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/21.jpg)
31
Match? - No! C CH2OH C CO
H
Substrate Principle transformations Metabolites
Aliphatic C-oxidation
C CH3 C CH2OH
Epoxidation
C C C C
O
C C
O
C C OHHO
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
P= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
Aliphatic C-oxidationCH2C CH3
P= 0.97
Epoxide Hydration
- Isopropenylbenzene
![Page 22: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/22.jpg)
32
C CH2OH C C
O
H
Substrate Principle transformations Metabolites
P= 0.97
Aliphatic C-oxidation
C CH3 C CH2OH
Epoxidation
C C C C
O
C C
O
C C OHHO
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
P= 0.94
P= 0.93
P= 0.90
P= 0.95
CH2C CH3
P= 0.96
Aliphatic C-oxidation
Epoxide Hydration
- Isopropenylbenzene
![Page 23: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/23.jpg)
33
Match? - No! C C
O
HO C C OH
Substrate Principle transformations Metabolites
C CH2OH C C
O
H
Aliphatic C-oxidation
C CH3 C CH2OH
Epoxidation
C C C C
O
Aliphatic C-oxidation
C C
O
HC C
O
OH
C OH C O
O
HOH H
OH
H
OHH
COOH
H
P= 0.94
P= 0.95
CH2C CH3
P= 0.93
P= 0.90
O-Glucuronidation
P= 0.96
Aliphatic C-oxidation
Epoxide Hydration
P= 0.97
- Isopropenylbenzene
![Page 24: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/24.jpg)
34
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
RESULTMatch? - Yes!C
H2CCH3
OC
H2C CH3
P= 0.95
C CH2OH C C
O
H
Aliphatic C-oxidation
C C
O
C C OHHOP= 0.96
Epoxide Hydration
Aliphatic C-oxidation
C CH3 C CH2OH
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
P= 0.94
P= 0.93
P= 0.90
P= 0.97
Generated map
1.1
Epoxidation
- Isopropenylbenzene
![Page 25: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/25.jpg)
35
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
RESULTMatch? - Yes!
CH2C CH3
C CH3 C CH2OH
CC CH2OHH2
P= 0.94
C CH2OH C C
O
H
Aliphatic C-oxidation
P= 0.96
Epoxide Hydration
C C
O
C C OHHO
Epoxidation
C C C C
O
P= 0.95
Aliphatic C-oxidation
C C
O
HC C
O
OH
C OH C O
O
HOH H
OH
H
OHH
COOH
H
P= 0.93
P= 0.90
O-Glucuronidation
P= 0.97
- Isopropenylbenzene
1.1
C-oxidation
1.2
Generated map
Epoxidation
![Page 26: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/26.jpg)
36
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
C CH2OH C C
O
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
C C
O
C C OHHO
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
Match?
CH2C CH3
C CH3 C CH2OH
- No!
P= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
Generated map
Epoxidation C-oxidation
- Isopropenylbenzene
1.1 1.2
![Page 27: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/27.jpg)
37
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
C CH2OH C C
O
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
C C
O
C C OHHO
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
Match?
CH2C CH3
- No!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
Generated map
Epoxidation C-oxidation
- Isopropenylbenzene
1.1 1.2
![Page 28: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/28.jpg)
38
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
C CH2OH C C
O
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
C C
O
C C OHHO
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
Match? - No!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
Generated map
Epoxidation C-oxidation
1.1 1.2
CH2C
OCH3
- Metabolite 1.1
![Page 29: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/29.jpg)
39
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
C CH2OH C C
O
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
Match?- Yes!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
CH2C
OCH3
C C
O
HO C C OH RESULT
C OH
OH
CH2
1.1 1.2
2.1
Hydration
C-oxidationEpoxidation
Generated map- Metabolite 1.1
![Page 30: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/30.jpg)
40
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
Match?- Yes!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
1.1 1.2
RESULTC OH
OH
CH2
- Metabolite 2.1
C C
O
C C OHHO
C CH2OH C CO
H
C OH
O
CH2
1.1 1.2
2.1
Generated map
Epoxidation C-oxidation
3.1
C-oxidation
Hydration
![Page 31: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/31.jpg)
41
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
Match?- Yes!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
1.1 1.2
RESULT
C C
O
C C OHHO
C CH2OH C CO
H 1.1 1.2
2.1
Generated map
Epoxidation C-oxidation
3.1
C-oxidation
Hydration
- Metabolite 1.2.
CC CH2OHH2 O
C
HCCH2
C-oxidation2.2
![Page 32: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/32.jpg)
42
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
Match?- No!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
1.1 1.2
C C
O
C C OHHO
1.1 1.2
2.1
Generated map
Epoxidation C-oxidation
3.1
C-oxidation
Hydration
- Metabolite 2.2.
OC
HCCH2
C-oxidation2.2
C CH2OH C C
O
H
![Page 33: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/33.jpg)
43
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
C C
O
C C
Epoxidation
Match?- No!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.95
P= 0.96
P= 0.97
1.1 1.2
C C
O
C C OHHO
1.1 1.2
2.1
Generated map
Epoxidation C-oxidation
3.1
C-oxidation
Hydration
OC
HCCH2
C-oxidation2.2
C CH2OH C C
O
H
- Metabolite 2.2.
![Page 34: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/34.jpg)
44
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
Epoxidation
Match?- Yes!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.96
P= 0.97
1.1 1.2
C C
O
C C OHHO
1.1 1.2
2.1
Generated map
Epoxidation C-oxidation
3.1
C-oxidation
Hydration
OC
HCCH2
C-oxidation2.2
C CH2OH C C
O
H
C C
O
C C
(Conjugated aldehyde group prevents epoxidation)
- Metabolite 2.2.
![Page 35: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/35.jpg)
45
Aliphatic C-oxidation
C C
O
HC C
O
OH
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
Epoxidation
Match?- No! C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.96
P= 0.97
1.1 1.2
C C
O
C C OHHO
1.1 1.2
2.1
Generated map
Epoxidation C-oxidation
3.1
C-oxidation
Hydration
OC
HCCH2
C-oxidation2.2
C CH2OH C C
O
H
C C
O
C CP= 0.95
- Metabolite 2.2.
![Page 36: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/36.jpg)
46
Aliphatic C-oxidation
O-Glucuronidation
C OH C O
O
HOH H
OH
H
OHH
COOH
H
Epoxide Hydration
Aliphatic C-oxidation
Aliphatic C-oxidation
Substrate Principle transformations Metabolites
Epoxidation
Match?- Yes!
C CH3 C CH2OHP= 0.94
P= 0.93
P= 0.90
P= 0.96
P= 0.97
1.1 1.2
C C
O
C C OHHO
1.1 1.2
2.1
Generated map
Epoxidation C-oxidation
3.1
C-oxidation
Hydration
OC
HCCH2
C-oxidation2.2
C CH2OH C C
O
H
C C
O
C CP= 0.95
C C
O
H
C C
O
OH
RESULT
OC
CCH2
OH
3.2
C-oxidation
- Metabolite 2.2.
![Page 37: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/37.jpg)
Metabolic SimulatorsBridging the “Parent Gap”
Virtual metabolism uses a heuristic substructure search engine applied to a hierarchy of possible molecular transformations
Library ofBiotransformations& Abiotic Reactions
Documented Partial Maps
Algorithm for optimizingTransformationProbabilities
(Rate constants)
MetabolicMaps and ReactivityProfiles
Metabolic Simulators
ParentChemicals
![Page 38: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/38.jpg)
Simulated Metabolic Activation of 2-AcetylaminofluoreneSimulated Metabolic Activation of 2-Acetylaminofluorene(AMES mutagenicity in Rat liverS9)(AMES mutagenicity in Rat liverS9)
NH
O
NH
O
OH
NH
O
O
NH2
O
HO
O
NHOH
O
N+HO
NH
OHO
NH
O
O
NH
O
O
NH
OHO
NH
OHO
OHNH
OHO
OH
NH
OHO
O
NH
OHO
O
N+H
HO
ON+H
OH
O
. . . . . .
NHX
OO
X = H, OH,
O
Activated metabolites
Documented
![Page 39: Predicting Indirect DNA Damage by Simulating Metabolic Activation of Chemicals](https://reader036.vdocument.in/reader036/viewer/2022070407/5681438c550346895db009a1/html5/thumbnails/39.jpg)
The OASIS Simulators of Mammalian Metabolism
•Liver S9 metabolism
•Different level of biological organisms (US EPA)Rat liver subcellular (microsomal)Rat liver cellular (in vitro)Organism (in vivo)
•In vivo metabolism – rat liver (in vivo MNT)In vivo detoxification logicIn vivo bioactivation
•Skin metabolism