Diol epoxides tumorigenicity

Comparison of Predicted Chemical Reactivity of Bay-Region Diol Epoxides with Approximate Tumorigenicity of the Parent Hydrocarbon0... 

Chang RJ, Levin W, Wood AW, Kumar S, Yagi H, Jerina DM, Lehr RE, Conney AH (1984) Tumorigenicity of dihydrodiols and diol-epoxides of benz[c] acridines in newborn mice. Cancer Res 44 5161-5164... 

Continued studies from several laboratories of the binding, mutagenicity and tumorigenicity of benzo [a] pyrene and its derivatives led to the identification of (+)-(7R,8S)-dihydroxy-(9S,10R)-epoxy-7,8,9,10-tetrahydrobenzo[aJpyrene (a diol epoxide-2 diastereomer) as the principal metabolite responsible for the carcinogenic activity of benzo[a]pyrene. Only one of the four metabolically possible isomers of the 7,8-diol-9,10-epoxide was found to have high tumorigenic activity... 

Levin W, Chang RL, Wood AW, et al. 1984. High stereoselectivity among the optical isomers of the diastereomeric bay-region diol-epoxides of benz(a)anthracene in the expression of tumorigenic activity in murine tumor models. Cancer Res 44 929-933. 

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. 

A.H. (1978) Tumorigenicity studies with diol-epoxides of benzo[a]pyrene whichindicatethat(+)-trans-7P,8a-dihydroxy-9 a,l 0a-epoxy-7,8,9,l 0-tetrahydrobenzo [ojpyrene is an ultimate carcinogen in newborn mice. Cancer Res., 38,... 

Xie, X.M., Geadntov, N.E., and Broyde, S. (1999) Stereochemical origin of opposite orientations in DNA addurts derived from enantiomeric anti-benzo[a] pyrene diol epoxides with different tumorigenic potentials. Biochemistry, 38, 2956-2968. 

Marky, L.A., Rentzeperis, D., Luneva, N.P., Cosman, M., Geadntoy, N.E., and Kupke, D.W. (1996) Differential hydration thermodynamics of stereoiso-meric DNA-benzo[a]pyrene adducts derived from diol epoxide enantiomers with different tumorigenic potentials. 

Geadntov, N.E., and Sdcchitano, D.A. (2003) Human RNA polymerase II is partially blocked by DNA adducts derived from tumorigenic benzojc] phenanthrene diol epoxides relating biological consequences to conformational preferences. Nucleic Acids Res.,... 

The novel bay-region diol epoxide isomers (93) have proved to be remarkably biologically active, despite their relative lack of reactivity towards hydrolysis (as expected from simple PMO calculations). Both diastereo-isomers prefer the conformation in which the OH groups are quasi-diequatorial, and these are the most tumorigenic diol epoxides yet tested on mouse skin. 

In 1988, O Brien (27A82a) discussed the fate of free radicals and their effect on chemical carcinogenesis. Only one comment was included on cigarette smoke and it involved the PAH B[fl]P in MSS and the assertion of its involvement in lung cancer induction. O Brien stated that PAHs like B[a]P donate a single electron to an enzyme which may be involved in the generation of tumorigenic diol-epoxides of the PAH. 

Diol epoxide metabolites of DMBA such as tra 5-3,4-dihydroxy-a //-1,2-epoxy-1,2,3,4-tetrahydro-DMBA (41) or rra 5-3,4-dihydroxy-s y -1,2-epoxy-1,2,3,4-tetrahydro-DMB A (42) has been implicated as the principle active form of DMBA which binds covalently to DNA in vivo. The intermediacy of 41 and 42 was further supported by the development of methods for their synthesis by using the Bradsher cyclization for the construction of the DMBA moiety, coupled with studies of their mutagenicity, tumorigenicity and DNA binding. ... 

Benz(a)anthracene-3,4-diol-1,2-epoxide (BADE) is a potent carcinogen [74-76] that metabolizes stereochemically and results in enantioselec-tive toxicities. The tumorigenic activities of benz(a)anthracene (BA), the (-1-)- and (—)-enantiomers of fra s-3,4-dihydroxy-3,4-dihydrobenz(a)anth-racene (BA-3,4-dihydrodiol) and the racemic diastereomers of the BA-3,4-diol-1,2-epoxides - that is, either or both of the diastereomeric 1,2-epoxides derived from BA-3,4-dihydrodiol, in which the epoxide oxygen is cis-(diol epoxide-1) or trans- (diol epoxide-2) to the benzylic 4-hydroxyl group-were examined in newborn Swiss-Webster mice by Wislocki etal. [77]. The mice were administered a total dose of 280 nmoles of compound, in divided doses consisting of 40 nmoles within 24 h of birth, 80 nmoles at 8 days of age, and 160 nmoles at 15 days of age. The experiment was terminated when the animals were 26 weeks of age. BA-3,4-diol-l,2-epoxide-2 was the most potent compound tested. All of... 

Tumorigenicity of tetrahydroepoxides. As yet, only Ch H -epoxide has been directly demonstrated to be tumorigenic (18). However, indirect evidence has been found in the high tumorigenicity of 3,4-dihydro BA, 9,10-dihydro BeP and 3,4-dihydrobenz[c]acridine (19-21), each of which is a likely metabolic precursor of a bay-region H -epoxide. In the case of 9,10-dihydro BeP, cis- and trans-9,10-dihydroxy -9,10,11,12-tetrahydro BeP were identified as products of metabolism of 9,10-dihydro BeP (22), and are the expected products of hydration of the epoxide. Diols are also formed from 7,8-dihydro BaP upon metabolism with prostaglandin endoperoxide synthase (23) or with rat liver homogenates (24). 

The relative stability of l, 2 -epoxyvinylbital, and the great instability of its diol, can be gainfully compared with the fate of the corresponding metabolites of phenyl vinyl ether (10.69, R = H) and 4-nitrophenyl vinyl ether (10.69, R = N02), two mutagenic and tumorigenic compounds [144] [145]. Their primary metabolic route is by vinyl epoxidation to the corresponding... 

Chang RL, Levin W, Wood AW, et al. 1981. Tumorigenicity ofthe diastereomeric bay-region benzo(e)pyrene 9,10-diol-11,12-epoxides in newborn mice. Cancer Res 41 915-918. 

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