Chrysene 1,2-diol

For example, polyclonal antibody 29.(12) obtained from animals immunized with BPDE-I-DNA, recognizes DNA modified by chrysene-1,2-diol-3,4-epoxide more efficiently (50 inhibition at 18 fmol) than it recognizes BPDE-I-DNA (50 inhibition at 30 fmol). This antibody also binds to DNA modified by benz(a)anthracene-8,9-diol-10,11-epoxide (50 Inhibition at 42 fmol) and 3,4-diol-l,2-epoxide (50 inhibition at 114 fmol). These results indicate that multiple adducts may be detected by the ELISA. Since humans are exposed to BP in complex mixtures containing a number of other PAHs, a nuBd>er of different adducts may be present. The Identity of the adducts cannot be determined and thus absolute quantitation of abducts is not possible. However, since a number of PAHs in addition to BP are... 

Weston et al. studied the metabolism and activation of a polycycKc aromatic hydrocarbon, chrysene, in mouse, rat, and human skin, employing a short-term organ culture technique. Upon examination of the stereochemistry of the metabolic product, chrysene-1,2-diol was formed in each... 

Table 4.10 The enantioselective tmnorigenicity of the enantiomers of /ra s-l,2-dihydro-xy-1,2-dihydrochrysene (chrysene-l,2-dihydrodiol) and chrysene-1,2-diol-3,4-epoxides on mouse skin [73]...

Day BW, Skipper PL, Wishnok JS, et al. 1990. Identification of an in v/Vo chrysene diol epoxide adduct in human hemoglobin. Chem Res Toxicol 3(4) 340-343. 

Substrates GSTM1 -1—Trans-stilbene oxide, DCNB-high, CDNB-mod-erate, Aflatoxin Bl-exo 8,9-epoxide, androstene 3,17-dione, B(a)P-diol epoxide, B(fl)P-4,5-oxide, chrysene diol epoxide, cumene hydroperoxide, ethacrynic acid, -nitrophenyl acetate, PGA2, PGJ2, styrene 7,8-oxide, fran5-4-phenyl-3-buten-2-one. 

Methods for the synthesis of the biologically active dihydrodiol and diol epoxide metabolites of both carcinogenic and noncarcinogenic polycyclic aromatic hydrocarbons are reviewed. Four general synthetic routes to the trans-dihydrodiol precursors of the bay region anti and syn diol epoxide derivatives have been developed. Syntheses of the oxidized metabolites of the following hydrocarbons via these methods are described benzo(a)pyrene, benz(a)anthracene, benzo-(e)pyrene, dibenz(a,h)anthracene, triphenylene, phen-anthrene, anthracene, chrysene, benzo(c)phenanthrene, dibenzo(a,i)pyrene, dibenzo(a,h)pyrene, 7-methyl-benz(a)anthracene, 7,12-dimethylbenz(a)anthracene, 3-methylcholanthrene, 5-methylchrysene, fluoranthene, benzo(b)fluoranthene, benzo(j)fluoranthene, benzo(k)-fluoranthene, and dibenzo(a,e)fluoranthene. 

Chrysene is a weak tumor initiator and is inactive as a complete carcinogen (38). The 1,2-dihydrodiol is more active as a mutagen than the 3,4- or the 5,6-dihydrodiols. The biological data support the hypothesis that the principal active metabolite of chrysene is the bay region anti-1,2-diol-3,4-epoxide (58). 

Epoxidation of 10 with m-chloroperbenzoic acid yielded the chrysene anti-1,2-diol-3,4-epoxide, whereas similar reaction of 11 gave a mixture of the corresponding anti and syn diol epoxides in a 5 3 ratio (57,59). These findings are in accord with previous observations that dihydrodiols free to adopt the diequatorial conformation undergo anti stereospecific epoxidation, whereas bay region diaxial dihydrodiols yield mixtures of anti and syn diastereomers. The syn-... 

An alternative new synthetic approach to chrysene 1,2-dihydro-diol based on Method IV has recently been developed (60). This method (Figure 12) entails synthesis of 2-chrysenol via alkylation of 1-1ithio-2,5-dimethoxy-1,4-cyclohexadiene with 2-(1-naphthyl) e-thyl bromide followed by mild acid treatment to ge nerate the diketone 12. Acid-catalyzed cyclization of 12 gave the unsaturated tetracyclic ketone 13 which was transformed to 2-chrysenol via dehydrogenation of its enol acetate with o-chloranil followed by hydrolysis. Oxidation of 2-chrysenol with Fremy s salt gave chrysene... 

Figure 11. Synthesis of the chrysene 1,2- and 3,4-dihydrodiols and the corresponding diol epoxide derivatives from chrysene by Method III (50. Reagents (i) H2,Pd (ii) H2,Pt (iii) DDQ (iv) AgOBZ,I25 (v) NBS A.

The carcinogenicity of PAH with relativelyTigh IP, such as benzo[c]phenanthrene, benz[a]anthracene, chrysene, 5-methyl chrysene and dibenz[a,h]anthracene (Table I), can be related to the formation of bay-region diol epoxides catalyzed by monooxygenase enzymes (j>). However, the most potent carcinogenic PAH have IP < ca. 7.35 eV. 

These findings indicate that PGH synthase in the presence of arachidonate can catalyze the terminal activation step in BP carcinogenesis and that the reaction may be general for dihydrodiol metabolites of polycyclic hydrocarbons. Guthrie et. al. have shown that PGH synthase catalyzes the activation of chrysene and benzanthracene dihydrodiols to potent mutagens (33). As in the case with BP, only the dihydrodiol that is a precursor to bay region diol epoxides is activated. We have recently shown that 3,4-dihydroxy-3,4-dihydro-benzo(a)anthracene is oxidized by PGH synthase to tetrahydrotetraols derived from the anti-diol epoxide (Equation 4) (34). 

Chrysene was mutagenic to Salmonella typhimurium in the presence of an exogenous metabolic system. It induced sister chromatid exchanges in one mouse study and chromosomal aberrations in one hamster study. Chrysene is metabolically activated to a 1,2-diol-3,4-epoxide that is mutagenic and carcinogenic in experimental animals and forms covalent adducts with DNA. ... 

Weems, H., Mushtaq, M., Fu, P., and Yang, S., Direct separation of non-k-region monool and diol enantiomers of phenanthrene, benz[a] anthracene, and chrysene by high-performance liquid chromatography with chiral stationary phases, J. Chromatogr., 371, 211, 1986. 

Analytical Properties Resolution of several enantiomers of polycyclic aromatic hydrocarbons, for example, chrysene 5,6-epoxide, dibenz[a,h]anthracene 5,6-epoxide, 7-methyl benz[a]anthracene 5,6-epoxide resolution of barbiturates, mephenytoin, benzodiazepinones, and succinimides direct separation of some mono-ol and diol enantiomers of phenanthrene, benz[a]anthrene, and chrysene ionically bonded to silica gel, this phase provides resolution of enantiomers of c/s-dihydroidiols of unsubstituted and methyl- and bromo-substituted benz[a]anthracene derivatives having hydroxyl groups that adopt quasiequatorial-quasiaxial and quasiaxial-quasiequatorial conformation Reference 31-35... 

The Suzuki cross-coupling reaction is recognized as a novel, abbreviated method for the synthesis of 2-hydroxychrysene, 2-hydroxy-5-methylchrysene, and 8-hydroxy-5-methyl-chrysene from easily accessible reactants (Eq. (8)) [23]. These phenolic compounds constitute precursors for the synthesis of dihydrodiol and bay-region diol epoxide derivatives of chrysene and 5-methylchrysene, which are implicated as the active forms of carcinogenic polynuclear aromatic hydrocarbons. 

DIBENZOCARBAZOLE see DCYOOO 7H-DIBENZO(c,g)CARBAZOLE see DCYOOO DIBENZO(b,def)CHRYSENE see DCY200 DIBENZO(def,p)CHRYSENE see DCY400 DIBENZO(def,p)CHRYSENE-l 1,12-DIOL, 11,12-DIHYDRO-, (11S,12S)-REL- see DDC810 DIBENZO-p-DIOXIN, 1,2,3,4,6,7,8-HEPTACHLORO-see HARIOO... 

Predicted and observed epoxidation of the enantiomeric chrysene 1,2-dihydrodiols to diastcreomeric bay-region diol epoxides. In this case, the same diastercotopic face of the dihydrodiol enantiomers is cpoxidized. Put in other terms, the specificity of cytochrome P450c is such that a single face of the dihydrodiol sub-strate(s) is cpoxidized regardless of the relative or absolute configuration of the hydroxyl groups. 

Apart from stereoselective bioactivation, stereoselective bioinactivation may be important too from a toxicological point of view. For instance, in contrast to the basic (a-e), the human near neutral ( i,) and acidic (tt) classes of GSH transferases were efficient in the conjugation of benz[aj-pyrene-7,8-diol-9,10-epoxides and, in particular, the carcinogenic (+)-anti-enantiomer (and other +)-flwh-enantiomers of the b -region diol-epoxides of ber z[a]anthracene and chrysene) (Jernstrom et al 1985 Robertson et al., 1986). 

The primary toxic effect of concern for chrysene is carcinogenicity, which is most likely the result of the mutagenic activity of its metabolites, 1,2-dihydrodiol and l,2-diol-3,4-epoxide. The 1,2-dihydrodiol and the l,2-diol-3,4-epoxide have been shown to be mutagenic in vitro in bacterial and mammalian cells and have induced pulmonary adenomas when administered to newborn mice. In addition, the 1,2-dihydrodiol was active as a tumor initiating agent on mouse skin. DNA adducts in hamster cells resulting from a reaction of the DNA with l,2-diol-3,4-exp-oxide have also been detected. 

Glatt H, Wameling C, Elsberg S, et al. 1993. Genotoxicity characteristics of reverse diol- epoxides of chrysene. Carcinogenesis 14(1) 11-19. 

Wood AW, Chang RL, Levin W, et al. 1979a. Mutagenicity and tumorigenicity of phenanthrene and chrysene epoxides and diol epoxides. Cancer Res 39 4069-4077. 

Amin, S., Desai, D., Dai, W., Harvey, R.G., and Hecht, S.S. (1995) Tumori-genicity in newborn mice of fjord region and other sterically hindered diol epoxides of benzo[g]chrysene, dibenzo[a,l]pyrene (dibenzo[de/p] chrysene), 4H -cyclopenta[de/]chrysene and fluoranthene. Carcinogenesis, 16, 2813-2817. 

Amin, S., Krzeminski, J., Rivenson, A., Kurtzke, C., Hecht, S.S., and El-Bay-oumy, K. (1995) Mammary cardno-genidty in female CD rats of fjord region diol epoxides of benzo[c] phenanthrene, benzo[g]chrysene and dibenzo[a,l]pyrene. Carcinogenesis, 16, 1971-1974. 

Robertson, 1. G. C, and JemstrSm, B., The enzymatic conjugation of glutathione with bay-region diol-epoxides of benzo(a)pyFene, benz(a)anthracene and chrysene. Carcinogenesis (London) 7, 1633-1636 (1986). 

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