Metabolisms (observed and simulated)
5 documented metabolism databases and 11 metabolic simulators are available in QSAR Toolbox.
Sometimes, metabolites and degradation products are cause of toxicity. QSAR Toolbox provides two types of metabolism – observed and simulated. All generated metabolites (documented and simulated) could be searched and profiled by the same approach as the parent chemicals and thus could inform the user about the potential formation of toxic metabolites. Additional information concerning the studied species and experimental conditions is provided for the observed metabolisms. The metabolic simulators imitating biotic (microbial, liver and skin metabolism), as well as abiotic (autoxidation, hydrolysis) transformations. Propagation of the simulated metabolism is confined objectively using parameters associated with the formal rate constants of metabolic transformations. Generation of metabolites is additionally reduced limiting the levels of metabolism; e.g. three levels of metabolism were found adequate to simulate rat liver S9 metabolism.
Metabolisms/transformations and basic information about them is provided in the table below.
| Metabolisms/ Transformations | Donator | Applicability to endpoint(s) (examples) | Documented metabolic maps | Number of molecular transformations | Additional information |
|---|
| Observed Mammalian metabolism | Laboratory of Mathematical Chemistry (LMC), Bourgas, Bulgaria | Genetic Toxicity (e.g. In vitro and In vivo - Gene Mutation, DNA Damage And/or Repair, DNA And/or Protein Damage in Liver, Chromosome Aberration, Transgenic Rodent Mutation) | 100 | N/A | In vivo and in vitro studies were used to analyze the metabolic fate of chemicals. Microsomes prevail over the other experimental systems included in the in vitro studies (around 50% of studies). Around 50% of administration routes included the in vivo studies refer to oral route of administration |
| Observed Microbial metabolism | Laboratory of Mathematical Chemistry (LMC), Bourgas, Bulgaria | Biodegradation (e.g. BOD, Primary Half-life, Total Biodegradation and Total Removal) | 587 | N/A | Most of catabolic pathways are related to aerobic conditions |
| Observed Rat In vivo metabolism | Laboratory of Mathematical Chemistry (LMC), Bourgas, Bulgaria | Genetic Toxicity (e.g. In vivo - Gene Mutation, DNA Damage And/or Repair, DNA And/or Protein Damage in Liver, Chromosome Aberration, Transgenic Rodent Mutation) | 647 | N/A | This metabolism is associated with the in vivo biotransformations of xenobiotic chemicals in rodents (mostly rats) |
| Observed rat liver metabolism with quantitative data | Laboratory of Mathematical Chemistry (LMC), Bourgas, Bulgaria | Genetic Toxicity (e.g. In vivo and In vitro - Gene Mutation, DNA Damage And/or Repair, DNA And/or Protein Damage in Liver, Chromosome Aberration, Transgenic Rodent Mutation | 49 | N/A | Included 13 chemicals with documented metabolic pathways and documented quantities |
| Observed Rat Liver S9 metabolism | Laboratory of Mathematical Chemistry (LMC), Bourgas, Bulgaria | Genetic Toxicity (e.g. In vitro - Gene Mutation, DNA Damage And/or Repair, Chromosome Aberration) | 261 | N/A | in vitro experimental systems such as rodent (mostly rat) liver microsomes and S9 fraction are used |
Simulated
| Metabolisms/ Transformations | Donator | Applicability to endpoint(s) (examples) | Documented metabolic maps | Number of molecular transformations | Additional information |
|---|
| Autoxidation simulator | Laboratory of Mathematical Chemistry (LMC), Bourgas, Bulgaria | Chemical reactivity (e.g. % Depletion of Cystein, GSH RC50), Sensitization (e.g. In chemico - % Depletion of Cystein, Adduct Formation; In vitro – EC3, CD54; In vivo - EC3, S M W N, ABC, NOEL, Respiratory sensitization) | N/A | 325 | The transformation reactions are divided into two groups oxidation reactions and considered as concomitant abiotic reactions |
| Autoxidation simulator (alkaline medium) | Laboratory of Mathematical Chemistry (LMC), Bourgas, Bulgaria | Chemical reactivity (e.g. % Depletion of Lysine), Sensitization (e.g. In chemico - % Depletion of Lysine) | N/A | 258 | The transformation reactions are divided into two groups oxidation reactions and considered as concomitant abiotic reactions |
| Dissociation simulator | Laboratory of Mathematical Chemistry (LMC), Bourgas, Bulgaria | Chemical reactivity (e.g. % depletion of Cystine, GSH RC50), Sensitization (e.g. In chemico - GSH RC50, Adduct Formation; In vitro - EC3, CD54; In vivo - EC3, S M W N, ABC, NOEL, Respiratory sensitization), Genetic Toxicity (e.g. In vitro and In vivo - Gene Mutation, DNA Damage And/or Repair, DNA And/or Protein Damage in Liver, Chromosome Aberration, Transgenic Rodent Mutation) and Repeated Dose Toxicity (e.g. NOEL, LOEL, LOEC, NOEC) | N/A | 81 | The most of transformation reactions are commonly related to the chemicals with ionic bond metals and nonmetals. The simulator is empirical and do not commit to provide a degree of ionization or dissociation of chemicals. |
| Hydrolysis simulator (acidic) | Laboratory of Mathematical Chemistry (LMC), Bourgas, Bulgaria | Chemical reactivity (e.g. % depletion of Cystine, GSH RC50), Sensitization (e.g. In chemico - GSH RC50, % depletion of Cystine), Absorption (e.g. CaCO2 (Papp), Human Intestinal Absorption, BBB partitioning, Clearance) | N/A | 75 | The development of the simulator is based on 341 chemicals with kinetic data for acidic catalyzed hydrolysis rate constant and observed hydrolysis products |
| Hydrolysis simulator (basic) | Laboratory of Mathematical Chemistry (LMC), Bourgas, Bulgaria | Chemical reactivity (e.g. % depletion of Cystine, GSH RC50), Sensitization (e.g. In chemico - GSH RC50, % depletion of Cystine) | N/A | 78 | The development of the simulator is based on 341 chemicals with kinetic data for basic catalyzed hydrolysis rate constant and observed hydrolysis products. |
| Hydrolysis simulator (neutral) | Laboratory of Mathematical Chemistry (LMC), Bourgas, Bulgaria | Chemical reactivity (e.g. % depletion of Cystine, GSH RC50), Sensitization (e.g. In chemico - GSH RC50, Adduct Formation; In vitro - EC3, CD54; In vivo - EC3, S M W N, A B C, NOEL, Respiratory sensitization), Repeated Dose Toxicity (e.g. NOEL, LOEL, LOEC, NOEC), Absorption (e.g. CaCO2 (Papp), Human Intestinal Absorption, BBB partitioning, Clearance) | N/A | 250 | The development of the simulator is based on 1128 chemicals with kinetic data for neutral hydrolysis rate constant (778 chemicals are with proprietary kinetic data) and observed hydrolysis products |
| in vivo Rat metabolism simulator | Laboratory of Mathematical Chemistry (LMC), Bourgas, Bulgaria | Repeated Dose Toxicity (e.g. NOEL, LOEL, LOEC, NOEC), Genetic Toxicity (e.g. In vivo - Gene Mutation, DNA Damage And/or Repair, DNA And/or Protein Damage in Liver, Chromosome Aberration, Transgenic Rodent Mutation), Carcinogenicity (Summary carcinogenicity, TD50), Absorption (e.g. CaCO2 (Papp), Human Intestinal Absorption, BBB partitioning, Clearance) | N/A | 716 | The molecular transformations set consist partly of 30 - 40 abiotic (non-enzymatic) and 630 - 640 enzyme-controlled reactions, from which 520 - 530 are enzymatic Phase I and the rest 100 - 110 are enzymatic Phase II transformation reactions. |
| Microbial metabolism simulator | Laboratory of Mathematical Chemistry (LMC), Bourgas, Bulgaria | Biodegradation | N/A | 930 | The microbial metabolism included multiple pathway catabolism simulation reactions which using the abiotic and enzyme-mediated reactions |
| Rat liver S9 metabolism simulator | Laboratory of Mathematical Chemistry (LMC), Bourgas, Bulgaria | Genetic Toxicity (e.g. In vitro - Gene Mutation, DNA Damage And/or Repair, Chromosome Aberration, Transgenic Rodent Mutation), Carcinogenicity (Summary carcinogenicity, TD50) | N/A | 561 | The molecular transformations set consists partly of 40 - 50 abiotic reactions Additionally, the simulator contains also 450 - 460 enzymatic Phase I transformations, such as aliphatic C-oxidation, aromatic C-hydroxylation, oxidative N- and O-dealkylation and etc. Moreover, 40 - 50 enzymatic Phase II transformations. |
| Skin metabolism simulator | Laboratory of Mathematical Chemistry (LMC), Bourgas, Bulgaria | Sensitization (e.g. In vitro - EC3, CD54; In vivo - EC3, S M W N, A B C, NOEL, SWAN) | N/A | 325 | The transformations are divided into two main types – rate-determining and non-rate-determining. The rate-determining transformations are Phase I and Phase II, such as C-hydroxylation, ester hydrolysis, glutathione conjugation, etc. The non-rate-determining transformations include hydrolysis of salts and molecular transformations of highly reactive intermediates. Currently, the simulator is upgraded and adjusted to simulate the documented in vitro metabolism of 181 chemicals. |
| Tautomerism | Laboratory of Mathematical Chemistry (LMC), Bourgas, Bulgaria | N/A | N/A | N/A | The new tautomer generation algorithm is implemented, locates the sites of possible hydrogen shifts and generates all possible combinations. |