Metabolic activation, benzo pyrene

Gelboin, H. (1980) Benzo[a]pyrene metabolism, activation, and carcinogenesis Role and regulation of mixed functional oxidases and related enzymes. Physiol. Rev. 60, 1107-1166. 

Livingstone DR, SV Farrar (1984) Tissue and subcellular distribution of enzyme activities of mixed-function oxygenase and benzo[a]pyrene metabolism in the common mussel Mytilis edulis L. Sci Tot Environ 39 209-235. 

Cremonesi P, EL Cavalieri, EG Rogan (1989) One-electron oxidation of 6-substituted benzo(a)pyrenes by manganic acetate. A model for metabolic activation. J Org Chem 54 3561-3570. 

A cytochrome P450 has been purified from Saccharomyces cerevisiae that has benzo[a]pyrene hydroxylase activity (King et al. 1984), and metabolizes benzo[fl]pyrene to 3- and 9-hydroxybenzo[fl]pyrene and benzo[fl]pyrene-7,8-dihydrodiol (Wiseman and Woods 1979). The transformation of PAHs by Candida Upolytica produced predominantly monohydroxyl-ated products naphth-l-ol from naphthalene, 4-hydroxybiphenyl from biphenyl and 3- and 9-hydroxybenzo[fl]pyrene from benzo[fl]pyrene (Cerniglia and Crow 1981). The transformation of phenanthrene was demonstrated in a number of yeasts isolated from littoral sediments and of these, Trichosporumpenicillatum was the most active. In contrast, biotransformation of benz[fl]anthracene by Candida krusei and Rhodotorula minuta was much slower (MacGillivray and Shiaris 1993). 

Figure 3. Structure of major DNA adduct detected in many in vivo systems as a result of metabolic activation of benzo[a]pyrene or the reaction of anti-B[alPDE with DNA jji vitro dR=deoxyribose moiety.

Sims, P. and P.L. Grover. 1981. Involvement of dihydrodiols and diol epoxides in the metabolic activation of polycyclic hydrocarbons other than benzo[a]pyrene. Pages 117-181 in H.V. Gelboin and P.O. Ts o (eds.). Polycyclic Hydrocarbons and Cancer. Vol. 3. Academic Press, New York. 

Varanasi, U. and D.J. Gmur. 1980. Metabolic activation and covalent binding of benzo[a]pyrene to deoxyribonucleic acid catalyzed by liver enzymes of marine fish. Biochem. Pharmacol. 29 753-762. 

Miller, A.G., Israel, D. and Whitlock, J.P., Jr (1983) Biochemical and genetic analysis of variant mouse hepatoma cells defective in the induction of benzo(a) pyrene-metabolizing enzyme activity. 

A. Metabolic activation of benzo(a)pyrene proceeds by a diol-epoxide. Nature (1974) 252 326-328. 

In general, biotransformation reactions are beneficial in that they facilitate the elimination of xenobiotics from pulmonary tissues. Sometimes, however, the enzymes convert a harmless substance into a reactive form. For example, CYP-mediated oxidation often results in the generation of more reactive intermediates. Thus, many compounds that elicit toxic injury to the lung are not intrinsically pneumotoxic but cause damage to target cells following metabolic activation. A classic example of this is the activation of benzo(a)pyrene, which is a constituent of tobacco smoke and combustion products, and is... 

Strueturally related adduets include the 8-phenol derivatives, 8-(4"-hydroxyphenyl)-dG (8-p-PhOH-dG), and 8-(2"-hydroxyphenyl)-dG (8-o-PhOH-dG) that are generated by reaetion of phenol with excess nitrite.This reaetion generates diazoquinones that break down into hydroxyphenyl radicals that attach covalently to C-8 of dG. Diazoquinones are mutagenic in the Ames test without metabolie aetivation, and it is expected that hydroxyphenyl radicals and the isomeric adducts, 8-p-PhOH-dG and 8-o-PhOH-dG, play a key role in the mutagenie activity of diazoquinones. Careinogenic PAHs, such as benzo[a]pyrene (BP), also form C8-dG adducts (8-BP-dG, Fig. 7). 2,173 hile classical metabolic activation of... 

Pelkonen, 0., Boobis, A.R., Levitt R.C., Kouri, R.E., and Nebert, D.W. (1979). Genetic differences in the metabolic activation of benzo[a]pyrene in mice. Attempts to correlate tumorigenesis with binding or reactive intermediates to DNA and with mutagenesis in vitro," Pharmacology 18,281. 

Examples of initiators include alkylating agents, dime thy lsu If ate and ji-propiolactone, procarcinogens (requiring metabolic activation) such as benzo(a)pyrene, aflatoxin, and cyclophosphamide (Fig. 6.52) as follows ... 

Figure 7.2 The metabolic activation of benzo[a]pyrene by cytochrome P-450 1A1 to a diol epoxide metabolite, a mutagen. This is believed to be the ultimate carcinogenic metabolite. Other routes of metabolism also catalyzed by cytochrome P-450 give rise to the 9,10, and 4,5 oxides and subsequent metabolites namely phenols, diols, and glutathione conjugates. The reactive site (carbon atom) on the metabolite is indicated.

The ultimate carcinogens arising from the metabolic activation of benzo(a)pyrene are stereoisomers of benzo(a)pyrene 7,8-diol-9,10-epoxide (Figure 7.3). These metabolites arise by prior formation of the 7,8 epoxide, which gives rise to the 7,8-dihydrodiol... 

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