Sulfotransferase-Mediated Activation of 7,8,9,10-Tetrahydro-7-ol, 7,8-Dihydrodiol, and 7,8,9,10-Tetraol Derivatives of Benzo[a]pyrene

Abstract

Some hydroxymethyl-substituted polycyclic aromatic hydrocarbons have been shown to be converted to electrophilic, mutagenic, or tumorigenic sulfuric acid ester metabolites by cytosolic sulfotransferase activity in rodent liver. Likewise, certain types of aromatic compounds with a secondary alcoholic functional group at the benzylic position undergo metabolic activation through sulfonation. Enzymatic oxidation of benzo[a]pyrene produces such secondary alcohols as dihydrodiol and tetraol derivatives as primary metabolites. Sulfo conjugation of the benzylic hydroxy group of each of these metabolites is expected to generate an electrophilic sulfuric acid ester capable of covalently binding to DNA, which may contribute to mutagenesis and carcinogenesis by benzo[a]pyrene. Although the model benzo-ring secondary benzyl alcohol, 7-hydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene, covalently bound to DNA and also exerted mutagenicity in the presence of rodent hepatic cytosols and 3'-phosphoadenosine 5'-phosphosulfate, no such sulfotransferase-dependent activation was observed with dihydrodiol or tetraol derivatives of benzo[a]pyrene. Thus, it seems likely that appearance of the adjacent non-benzylic hydroxy functional group(s) in latter metabolites hinders the benzylic sulfonation in these molecules.

Current Status of the Cytosolic Sulfotransferases in the Metabolic Activation of Promutagens and Procarcinogens

“…In addition, enzymatic oxidation of BP produces such secondary alcohols as dihydrodiol and tetrol derivatives as primary metabolites [23,82]. Although possible sulfuric acid ester metabolite formed with benzylic-OH group of each of these metabolites would be expected to generate an electrophilic sulfuric acid ester capable of covalently binding to DNA, no such SULT-dependent mutagenicity was observed with dihydrodiol or tetrol derivatives of BP [82].…”

“…In addition, enzymatic oxidation of BP produces such secondary alcohols as dihydrodiol and tetrol derivatives as primary metabolites [23,82]. Although possible sulfuric acid ester metabolite formed with benzylic-OH group of each of these metabolites would be expected to generate an electrophilic sulfuric acid ester capable of covalently binding to DNA, no such SULT-dependent mutagenicity was observed with dihydrodiol or tetrol derivatives of BP [82]. However, the model benzo-ring reduced secondary benzylic alcohol, 7-OH-7,8,9,10-tetrahydro-BP (7-OH-H 4 -BP), covalently bound to DNA and exerted mutagenicity in the presence of rodent hepatic cytosols and PAPS [51,82].…”

“…Although possible sulfuric acid ester metabolite formed with benzylic-OH group of each of these metabolites would be expected to generate an electrophilic sulfuric acid ester capable of covalently binding to DNA, no such SULT-dependent mutagenicity was observed with dihydrodiol or tetrol derivatives of BP [82]. However, the model benzo-ring reduced secondary benzylic alcohol, 7-OH-7,8,9,10-tetrahydro-BP (7-OH-H 4 -BP), covalently bound to DNA and exerted mutagenicity in the presence of rodent hepatic cytosols and PAPS [51,82]. Furthermore, another study indicated that BP-tetrols were activated by SULTs only at high substrate concentrations, and thus the importance of these metabolites to BP-mediated carcinogenicity was questioned [83].…”

Phenol sulphotransferase SULT1A1 polymorphism: molecular diagnosis and allele frequencies in Caucasian and African populations

“…The sulphate esters of, for example, hydroxyarylamines, arylhydroxamic acids and benzylic alcohols of polycyclic aromatic hydrocarbons are normally highly unstable, and decompose spontaneously to form extremely reactive species that adduct to DNA [8,13]. The requirement for sulphation in the activation of such chemicals can be demonstrated in i o and in itro [8,[14][15][16][17][18].…”

Phenol sulphotransferase SULT1A1 polymorphism: molecular diagnosis and allele frequencies in Caucasian and African populations

“…The sulphate esters of, for example, hydroxyarylamines, arylhydroxamic acids and benzylic alcohols of polycyclic aromatic hydrocarbons are normally highly unstable, and decompose spontaneously to form extremely reactive species that adduct to DNA [8,13]. The requirement for sulphation in the activation of such chemicals can be demonstrated in i o and in itro [8,[14][15][16][17][18].…”