Inhibition of the binding of 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene to DNA in mouse skin epidermis by 1-ethynylpyrene.
The effects of 1-ethynylpyrene (EP), 1-vinylpyrene (VP) and 2-ethynlnaphthalene (EN) on the covalent binding of 7,12-dimethylbenz[a]anthracene (DMBA) and of benzo[a]-pyrene (B[a]P) to the epidermal DNA in mouse skin were investigated. When applied topically, 5 min before an initiating dose of 10 nmol DMBA or of 200 nmol B[a]P, EP was an effective inhibitor of the formation of the covalent complexes of these procarcinogenic polycyclic aromatic hydrocarbons (PAHs) with the epidermal DNA. VP, applied under the same conditions, was a significantly less effective inhibitor of the binding of DMBA to DNA and showed even weaker inhibition of the binding of B[a]P. EN was ineffective as an inhibitor of the binding of either DMBA or B[a]P. These results establish that both the pyrene nucleus and the ethynyl substituent of EP contribute to the effective inhibition of the binding of DMBA and B[a]P to the epidermal DNA of mouse skin. No significant changes in the ratios of the anti- to the syndiol epoxide-DNA adducts of DMBA or of B[a]P were produced by doses of EP that produced inhibitions of the binding to DNA. At doses of VP that inhibited covalent binding of both DMBA and B[a]P, no changes in DMBA-DNA adduct distributions were observed but changes in the relative proportions of several B[a]P-DNA adducts were noted. These data are discussed in terms of the potential of aryl acetylenes to act as suicide inhibitors (mechanism-based inactivators) of cytochrome P450-dependent monooxygenase isozymes.
Viaje
A
A
University of Texas System Cancer Center, Science Park Research Division, Smithville 78957.
Lu
J Y
JY
Hopkins
N E
NE
Nettikumara
A N
AN
DiGiovanni
J
J
Alworth
W L
WL
Slaga
T J
TJ
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism*; D000287:Administration, Topical; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology; D011721:Pyrenes / Q000008:administration & dosage / Q000494:pharmacology*; D012867:Skin / Q000378:metabolism*
D009281:Naphthalenes; D011721:Pyrenes; C065011:1-vinylpyrene; C065012:2-ethynylnaphthalene; D001564:Benzo(a)pyrene; C042881:1-ethynylpyrene; D015127:9,10-Dimethyl-1,2-benzanthracene; D004247:DNA