Enzyme-Mediated Dialdehyde Formation:  An Alternative Pathway for Benzo[a]pyrene 7,8-Dihydrodiol Bioactivation

• Published in: Chemical research in toxicology 2000-11, Vol.13 (11), p.1174-1180
• Main Authors: Stansbury, Kevin H, Noll, David M, Groopman, John D, Trush, Michael A
• Format: Article
• Language: English
• Subjects: Aldehydes - blood; Aldehydes - metabolism; Aldehydes - pharmacokinetics; benzo(a)pyrene-7,8-dihydrodiol; Biotransformation; Carcinogens, Environmental - pharmacokinetics; Chromatography, High Pressure Liquid; Dihydroxydihydrobenzopyrenes - blood; Dihydroxydihydrobenzopyrenes - pharmacokinetics; dioxetane; Heterocyclic Compounds - analysis; Heterocyclic Compounds - metabolism; Humans; Hydrogen Peroxide - metabolism; Hydrogen Peroxide - pharmacology; Luminescent Measurements; Mass Spectrometry; Neutrophils - enzymology; Neutrophils - metabolism; Nuclear Magnetic Resonance, Biomolecular; Peroxidase - metabolism; Taurine - blood; Taurine - metabolism; Taurine - pharmacology
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx000159p

Polycyclic aromatic hydrocarbons, such as benzo[a]pyrene, are widespread environmental carcinogens of human concern. Several enzymatic systems have been shown to activate benzo[a]pyrene 7,8-dihydrodiol, the proximate carcinogenic metabolite of benzo[a]pyrene, to a reactive species which produces both a chemiluminescence response and genotoxic lesions. The chemiluminescence response has been proposed to be the result of the formation of a dioxetane which upon ring opening forms a reactive dialdehyde intermediate. In in vitro incubations involving phorbol ester-stimulated human polymorphonuclear leukocytes or an isolated enzyme system consisting of myeloperoxidase, taurine, and hydrogen peroxide, a prolonged (>60 min) chemiluminescence response was observed from benzo[a]pyrene 7,8-dihydrodiol. HPLC analysis of the reaction mixture revealed the existence of a product which is dependent upon both taurine and the hydrocarbon. Characterization of this product using UV, NMR, and MS indicated that the product is a pyrene with two side chains resulting from bond breakage of a ring, yielding a dialdehyde. These side chains contain a portion of taurine covalently attached through imine formation with the aldehydes resulting from dioxetane ring opening. Replacement of taurine with either protein or DNA also produced a prolonged chemiluminescence response. These results demonstrate for the first time the formation of a novel electrophilic species from benzo[a]pyrene 7,8-dihydrodiol which along with an increased production of photons from this activation mechanism may lead to DNA and/or protein damage that is different from that elicited by diol epoxides.