Dietary glucarate as anti-promoter of 7, 12-dimethylbenz[a]anthracene-induced mammary tumorigenesis

Abstract

Using as a criterion the inhibition of serum beta-glucuronidase activity, dietary calcium D-glucarate is shown to serve as an efficient slow-release source in vivo of D-glucaro-1,4-lactone, the potent endogenous inhibitor of this enzyme. Using the 7,12-dimethylbenz[a]anthracene model of mammary tumor induction in rats it is shown for the first time that feeding the rats calcium D-glucarate-supplemented diet after treatment with the carcinogen, inhibits tumor development by over 70%. Supportive evidence is presented for the theory that calcium D-glucarate inhibits or delays the promotion phase of mammary carcinogenesis by lowering endogenous levels of estradiol and precursors of 17-ketosteroids. Therefore, dietary glucarate can be used to lower blood and tissue levels of beta-glucuronidase, and in turn of those carcinogens and promoting agents which are excreted, at least in part, as glucuronide conjugates.

Putative metabolites derived from dietary combinations of calcium glucarate and N-(4-hydroxyphenyl)retinamide act synergistically to inhibit the induction of rat mammary tumors by 7,12-dimethylbenz[a]anthracene.

“…Since CGT undergoes a slow partial conversion in the stomach to the potent B-glucuronidase inhibitor D-glucaro-1,4-lactone (12)(13)(14)(15), it is possible that CGT enhances the net glucuronidation of HPR, as was shown for bilirubin (15). Therefore, through enhancement of glucuronidation, CGT may cause longer retention of HPR in extrahepatic tissues, in general, and the mammary gland of the female rat, in particular.…”

“…This activity is believed to derive from the slow conversion of approximately one-third of the CGT to the potent f3-glucuronidase inhibitor D-glucaro-1,4-lactone, at the acid pH of the stomach. The increased net glucuronidation could theoretically lead to increased excretion of carcinogens and promoting agents, including steroid hormones, as glucuronide conjugates (12)(13)(14). Consequently, CGT has been observed to inhibit the initiation and promotion phases of tumorigenesis.…”

“…Studies from this laboratory have shown that dietary calcium glucarate (CGT) is an effective preventative chemical (chemopreventative) agent against cancer induction in several rodent organs, including the mammary gland (12,13). This activity is believed to derive from the slow conversion of approximately one-third of the CGT to the potent f3-glucuronidase inhibitor D-glucaro-1,4-lactone, at the acid pH of the stomach.…”

“…Approximately 4 hr prior to the completion of bile duct cannulation (PE-20 tubing, Clay Adams, Parsippany, NJ), the rats received by gavage (19-gauge feeding needle, Popper & Sons, New Hyde Park, NY) either 1.0 ml of the 10% (wt/vol) aqueous gum acacia vehicle or CGT [4.5 mmol/kg (body weight)] in 1.0 ml of 10% gum acacia. Timing may be important if f8-glucuronidase is involved since maximum inhibition is observed in tissues between 3 and 5 hr after administration of CGT (12). The cannula was externalized from the abdominal incision under the skin, exiting to a fraction collector through an incision in the intrascapular region.…”

β-Glucuronidase levels in patients with fibrocystic breast disease

“…In fact, we have identified 'sustained release precursors' of a potent natural [3-glucuronidase inhibitor, which when fed at time of chemical carcinogen administration dramatically reduces the induction of tumors in experimental animals [6,7]. Thus, inhibiting endogenous [3-glucuronidase causes a larger proportion of these compounds to be excreted in the urine and bile as glucuronides.…”