In vitro activation of isophosphamide and trophosphamide to metabolites mutagenic for bacteria

doi:10.1016/0378-4274(86)90124-4

Toxicology Letters

Volume 31, Issue 3, June 1986, Pages 183-188

https://doi.org/10.1016/0378-4274(86)90124-4 Get rights and content

Abstract

The ability of S9 liver fractions from uninduced rats to activate isophosphamide (IP) and trophosphamide (TP) to metabolites mutagenic for bacteria was compared to that of S9 fractions prepared from rats pretreated in vivo with three inducers of hepatic monooxygenase. Pretreatment of rats with phenobarbital (PB) and Aroclor 1254 increased IP and TP mutagenic activation by S9 fractions as compared to control and 3-methylcholanthrene (3-MC-induced rat liver S9. Furthermore, the effect of mixed-function oxidase inhibitors, such as α-naphthoflavone, metyrapone and SKF 525-A on S9-mediated mutagenic activation of IP and TP was investigated. The data obtained suggest the involvement of a PB-inducible form of cytochrome P-450 in the activation of IP and TP to mutagenic species.

References (26)

B.F. Hales et al.
Characteristics of the activation of cyclophosphamide to a mutagen by rat liver
Biochem. Pharmacol.
(1980)
B.F. Hales et al.
Effects of Phénobarbital and β-naphthoflavone on the activation of cyclophosphamide to mutagenic metabolites in vitro by liver and kidney from male and female rats
Biochem. Pharmacol.
(1980)
W.K. de Raat
The induction of sister chromatid exchanges by cyclophosphamide in the presence of differently induced microsomal fractions of rat liver
Chem.-Biol. Interact.
(1977)
D.M. Maron et al.
Revised methods for the Salmonella mutagenicity test
Mutation Res.
(1983)
O.H. Lowry et al.
Protein measurement with the Folin phenol reagent
J. Biol. Chem.
(1951)
T. Omura et al.
Carbon monoxide-binding pigment of liver microsomes, 1. Evidence for its hemoprotein nature
J. Biol. Chem.
(1964)
A.P. Alvares et al.
Heterogeneity of cytochrome P-450s induced by polychlorinated biphenyls
J. Biol. Chem.
(1977)
D. Ryan et al.
Highly purified cytochrome P-448 and P-450 from rat liver microsomes
Biochem. Biophys. Res. Commun.
(1975)
P.E. Thomas et al.
Multiple forms of rat-liver cytochrome P-450
J. Biol. Chem.
(1976)
D. Ryan et al.
Separation and characterization of highly purified forms of liver microsomal cytochrome P-450 from rats treated with polychlorinated biphenyls, phenobarbital and 3-methylcholanthrene
J. Biol. Chem.
(1979)

A. Banerjee et al.

Production of sister chromatid exchanges by various cancer chemotherapeutic agents

Cancer Res.

(1979)

W.F. Benedict et al.

Mutagenicity of cancer chemotherapeutic agents in the Salmonella/microsome test

Cancer Res.

(1977)

W.F. Benedict et al.

Induction of morphological transformation in mouse C3H/IOT $12$ clone 8 cells and chromosomal damage in hamster A(T₁)Cl-3 cells by cancer chemotherapeutic agents

Cancer Res.

(1977)

Cited by (7)

smProdrugs: A repository of small molecule prodrugs
2023, European Journal of Medicinal Chemistry
In modern drug discovery and development, the prodrug approach has become a crucial strategy for enhancing the pharmacokinetic profiles of drugs. A prodrug is a chemical compound, which gets metabolized into a pharmacologically active form (drug) inside the body after its administration. In the current work, we report ‘smProdrugs’ (http://cheminfolab.in/databases/prodrug/), which is one of the first exclusive databases on small molecule prodrugs. It stores the structures, physicochemical properties and experimental ADMET data manually curated from literature. SmProdrugs lists 626 small molecule prodrugs and their active compounds with the above mentioned experimental data from 1808 research articles and 61 patents have been stored. The information page of each record gives the structures and properties of the prodrug and the active drug side by side which makes it easy for the user to instantly compare them. The structural modifications in the prodrug/active drugs are highlighted in a different colour for easy comparison. Experimental data has been curated from the downloaded PubMed and patent articles and were catalogued in a tabular form with more than 25 fields under sub-sections i) name and structures of the prodrugs and their active compounds, ii) mode of activation of the prodrug and enzyme/biocatalyst involved in the conversion, iii) indications/disease, iv) pharmacological target, v) experimental pharmacokinetic properties such as solubility, absorption, volume of distribution, half-life, clearance etc. and vi) information on the purpose/gain from the prodrug strategies. Considering the ever expanding utility of the prodrug approach smProdrugs will be of great use to the scientific community working on rational design of small molecule prodrugs.
A core in vitro genotoxicity battery comprising the Ames test plus the in vitro micronucleus test is sufficient to detect rodent carcinogens and in vivo genotoxins
2011, Mutation Research - Genetic Toxicology and Environmental Mutagenesis
In vitro genotoxicity testing needs to include tests in both bacterial and mammalian cells, and be able to detect gene mutations, chromosomal damage and aneuploidy. This may be achieved by a combination of the Ames test (detects gene mutations) and the in vitro micronucleus test (MNvit), since the latter detects both chromosomal aberrations and aneuploidy. In this paper we therefore present an analysis of an existing database of rodent carcinogens and a new database of in vivo genotoxins in terms of the in vitro genotoxicity tests needed to detect their in vivo activity. Published in vitro data from at least one test system (most were from the Ames test) were available for 557 carcinogens and 405 in vivo genotoxins. Because there are fewer publications on the MNvit than for other mammalian cell tests, and because the concordance between the MNvit and the in vitro chromosomal aberration (CAvit) test is so high for clastogenic activity, positive results in the CAvit test were taken as indicative of a positive result in the MNvit where there were no, or only inadequate data for the latter. Also, because Hprt and Tk loci both detect gene-mutation activity, a positive Hprt test was taken as indicative of a mouse-lymphoma Tk assay (MLA)-positive, where there were no data for the latter. Almost all of the 962 rodent carcinogens and in vivo genotoxins were detected by an in vitro battery comprising Ames + MNvit. An additional 11 carcinogens and six in vivo genotoxins would apparently be detected by the MLA, but many of these had not been tested in the MNvit or CAvit tests. Only four chemicals emerge as potentially being more readily detected in MLA than in Ames + MNvit – benzyl acetate, toluene, morphine and thiabendazole – and none of these are convincing cases to argue for the inclusion of the MLA in addition to Ames + MNvit. Thus, there is no convincing evidence that any genotoxic rodent carcinogens or in vivo genotoxins would remain undetected in an in vitro test battery consisting of Ames + MNvit.
Induction of sperm abnormalities in mice by ifosfamide and trofosfamide
1988, Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
The antitumor drugs ifosfamide (IF) and trofosfamide (TF) were evaluated for their capability to induce sperm abnormalities in (C3H × C57BL/6)F₁ mice.
A statistically significant increase in teratospermia was observed at the 35th day after 5 daily consecutive intraperitoneal injections of the drugs at doses of 25, 50, 100 mg/kg b.w. of TF and 100 mg/kg b.w. of IF. Thus, IF and TF are able to interfere with the differentiation process of spermatogenic cells.
Enzyme-Catalyzed Activation of Anticancer Prodrugs
2004, Pharmacological Reviews
Induction of specific-locus and dominant lethal mutations in male mice by ifosfamide (Holoxan)
1998, Genetical Research
Trofosfamide: A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the oral treatment of cancer
1997, Anti-Cancer Drugs

View all citing articles on Scopus

View full text

In vitro activation of isophosphamide and trophosphamide to metabolites mutagenic for bacteria

Abstract

Biochem. Pharmacol.

Biochem. Pharmacol.

Chem.-Biol. Interact.

Mutation Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Production of sister chromatid exchanges by various cancer chemotherapeutic agents

Cancer Res.

Mutagenicity of cancer chemotherapeutic agents in the Salmonella/microsome test

Cancer Res.

Induction of morphological transformation in mouse C3H/IOT 12 clone 8 cells and chromosomal damage in hamster A(T1)Cl-3 cells by cancer chemotherapeutic agents

Cancer Res.

Induction of morphological transformation in mouse C3H/IOT $12$ clone 8 cells and chromosomal damage in hamster A(T₁)Cl-3 cells by cancer chemotherapeutic agents