Ellagic acid: a potent naturally occurring inhibitor of benzo[a]pyrene metabolism and its subsequent glucuronidation, sulfation and covalent binding to DNA in cultured BALB/C mouse keratinocytes

Abstract

The metabolism of [3H]benzo[a]pyrene (BP) by cultured primary keratinocytes prepared from BALB/C mouse epidermis was found to be largely inhibited by the dietary plant phenol, ellagic acid. Varying concentrations of ellagic acid added to the keratinocyte cultures resulted in a dose-dependent inhibition of the cytochrome P-450-dependent monooxygenases aryl hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin-O-deethylase (ECD). The major organic solvent-extractable metabolites found intracellularly in the cultured cells were trans-7,8-dihydro-7,8-dihydroxybenzo[a]-pyrene (BP-7,8-diol) and 3-hydroxybenzo[a]pyrene (3-OH-BP), although small amounts of 9-hydroxybenzo[a]pyrene, quinones and trans-9,10-dihydro-9,10-dihydroxybenzo[a]-pyrene (BP-9,10-diol) were also present. The major organic solvent-extractable metabolites found in the extracellular culture medium were BP-7,8-diol and BP-9,10-diol, with smaller quantities of unconjugated phenols and quinones. The major intracellular and extracellular water-soluble metabolites of BP were conjugated with glucuronide (primarily 3-OH-BP and several BP-quinones), and to a lesser extent with sulfate (primarily BP-7,8-diol). Both intracellular and extracellular metabolism of organic solvent-extractable and water-soluble conjugates was significantly inhibited by ellagic acid in a dose-dependent manner. The intracellular enzyme-mediated binding of BP to mouse keratinocyte DNA was also largely inhibited in a dose-dependent fashion by ellagic acid. Our results indicate that cultured primary mouse keratinocytes offer a useful model system for studying factors affecting the metabolic activation and detoxification of polycyclic aromatic hydrocarbon carcinogens in the epidermis, and that polyphenolic compounds such as ellagic acid may prove useful in modulating the risk of cutaneous cancer that results from exposure to these environmental chemicals.

Taurine and ellagic acid: Two differently‐acting natural antioxidants

“…In fact, Dixit and Gold [ 19861 and Barch and Fox [ 19881 showed that ellagic acid protects the 0 6 position of DNA guanine against the methylation capacity of MeNU and MBN; Lord et al [1989] showed no inhibitory effect of DMN mutagenicity. Furthermore, studies support the ability of ellagic acid to reduce the metabolism of some polycyclic aromatic hydrocarbons [Mukhtar et al, 1984;Das et al, 1985;Tee1 et al, 19851, but not of nitropyrene [Kuo et al, 19921, and to counteract their diol epoxide metabolites [Wood et al, 1982;Dixit et al, 1985;Josephy et al, 19901, inhibiting their binding to DNA.…”

Tannins, xenobiotic metabolism and cancer chemoprevention in experimental animals

“…Ellagic acid has been shown to lower total P450 content of rat hepatic (16), lung (16) and esophageal microsomes (17). It has also been shown to inhibit the bioactivation of procarcinogens which are metabolized by the P4501A family, including BaP, 3-methylcholathrene (3-MC), and the food mutagen 2-amino-3-methylimidazole [4,5-t] quinoline (IQ) (18)(19)(20). Furthermore, it has been reported that dietary ellagic acid significantly reduces total esophageal and hepatic P450 levels and the esophageal microsomal metabolism of NMBA (17).…”

Ellagitannins from Geranium potentillaefolium and G. bellum

“…Geraniin (1), upon hydrolysis in boiling water, gives corilagin (2), ellagic (3), gallic (4) and brevifolincarboxylic (5) acids in addition to glucose, while upon acid hydrolysis it provides 3 and 4 [8] (Figure 1). Compounds 1-5 have strong antioxidant activities [2][3][4][5], ellagic acid (3) is a potent inhibitor of benzo[a]pyrene metabolism [9], has activity against SUDHL1 and FEPD tumor cells, and is a casein kinase 2 inhibitor [10], and methyl gallate (6) inhibits the growth of B16 melanoma, L1210 and P388 tumor cells [11].…”