Enzyme-mediated dialdehyde formation: an alternative pathway for benzo[a]pyrene 7,8-dihydrodiol bioactivation.
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.
Stansbury
K H
KH
Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205, USA.
Noll
D M
DM
Groopman
J D
JD
Trush
M A
MA
D000447:Aldehydes / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D002274:Carcinogens, Environmental / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004101:Dihydroxydihydrobenzopyrenes / Q000097:blood / Q000493:pharmacokinetics*; D006571:Heterocyclic Compounds / Q000032:analysis / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D008163:Luminescent Measurements; D013058:Mass Spectrometry; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D009195:Peroxidase / Q000378:metabolism*; D013654:Taurine / Q000097:blood / Q000378:metabolism / Q000494:pharmacology
D000447:Aldehydes; D002274:Carcinogens, Environmental; D004101:Dihydroxydihydrobenzopyrenes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; C017228:benzo(a)pyrene 7,8-dihydrodiol; C079142:1,2-dioxetane; D013654:Taurine; D006861:Hydrogen Peroxide; D009195:Peroxidase