Exocyclic adducts of DNA bases, such as etheno- and hydroxyalkano- ones, are generated by a variety of bifunctional agents, including endogenously formed products of lipid peroxidation. In this work we selectively modified cytosines in the 5'-d(TTT TTT CTT TTT CTT TTT CTT TTT T)-3' oligonucleotide using: chloroacetaldehyde to obtain 3,N(4)-alpha-hydroxyethano- (HEC) and 3,N(4)-etheno- (epsilonC...

Ifosfamide nephrotoxicity is attributed to the formation of a toxic metabolite, chloroacetaldehyde, via N-dechloroethylation, a reaction that is purportedly catalyzed by CYP3A and CYP2B6. Because allelic variants of CYP3A5 are associated with polymorphic expression of microsomal CYP3A5 in human liver and kidneys, we hypothesized that ifosfamide N-dechloroethylation depends on CYP3A5 genotype. W...

The efficacy of ifosfamide (IFO), an antineoplastic drug, is severely limited by a high incidence of nephrotoxicity of unknown etiology. We hypothesized that inhibition of complex I (C-I) by chloroacetaldehyde (CAA), a metabolite of IFO, is the chief cause of nephrotoxicity, and that agmatine (AGM), which we found to augment mitochondrial oxidative phosphorylation and beta-oxidation, would prev...

An Investigation of the Role of Microsomal Oxidative Metabolism in the in Vivo Genotoxicity of 1,2-Dichloroethane. STORER, R. D.. AND CONOLLY, R. B. (1985). Toxicol. Appl. Pharmacol. 77,36-46. In vitro studies have demonstrated that two different metabolic pathways, glutathione conjugation mediated by the glutathione S-transferases and microsomal oxidation, may be involved in the genotoxicity a...

Oxidative stress enhances lipid peroxidation (LPO) implicated in the promotion and progression of carcinogenesis. One of the major LPO products is trans-4-hydroxy-2-nonenal (HNE), may to react with guanosine and under peroxidizing conditions also with adenosine. Additionally the same effect may induce environmental carcinogens, e.g. vinyl chloride and its metabolite chloroacetaldehyde (CAA). Th...

Cyclophosphamide (CPA) and ifosfamide (IFA) are oxazaphosphorine anticancer prodrugs metabolized by two alternative cytochrome P450 (P450) pathways, drug activation by 4-hydroxylation and drug inactivation by N-dechloroethylation, which generates the neurotoxic and nephrotoxic byproduct chloroacetaldehyde. CPA and IFA metabolism catalyzed by P450s 2B1, 2B4, 2B5, and seven site-specific 2B1 muta...

Chloroacetaldehyde (CA) is a nephrotoxic and neurotoxic metabolite of the anticancer drug ifosfamide (IFA) and is a dose-limiting factor in IFA-based chemotherapy. Plasma levels of CA in IFA-treated cancer patients are often difficult to determine due to the lack of a sufficiently sensitive and specific analytical method. We have developed a simple and sensitive HPLC method with fluorescence de...

BACKGROUND ALKBH proteins, the homologs of Escherichia coli AlkB dioxygenase, constitute a direct, single-protein repair system, protecting cellular DNA and RNA against the cytotoxic and mutagenic activity of alkylating agents, chemicals significantly contributing to tumor formation and used in cancer therapy. In silico analysis and in vivo studies have shown the existence of AlkB homologs in a...

The traditional Chinese medicine Schisandra chinensis has remarkable protective effects against chemical-induced toxicity. Cyclophosphamide (CTX), in spite advances in chemotherapy and immunosuppressive regimes, is prone to cause severe toxicity due to its chloroacetaldehyde (CAA) metabolite produced by CYP3A. Our previous study identified that S. chinensis extract (SCE) co-administration poten...

Adenosine (ADO) has an antiadrenergic action in the heart that causes an attenuation of contractile and metabolic responses elicited by fi-adrenergic stimulation. The effect of an increase in oxygen consumption elicited by either f-adrenergic stimulation or an increase in contraction frequency on interstitial fluid and coronary effluent ADO levels was investigated in isolated perfused isovolumi...