Metabolism, uptake, and excretion of a D-glucaric acid salt and its potential use in cancer prevention.
D-Glucaric acid (GA) is a nontoxic, natural compound. One of its derivatives is the potent beta-glucuronidase inhibitor D-glucaro-1,4-lactone (1,4-GL). The goal of this study was to demonstrate the in vivo formation of 1,4-GL from a D-glucarate salt and determine its metabolism, uptake by selected organs, and excretion following oral administration of potassium hydrogen D-[14C]glucarate to male and female Sprague-Dawley rats. 1,4-GL increases detoxification of carcinogens and tumor promoters/progressors by inhibiting beta-glucuronidase and preventing hydrolysis of their glucuronides. 1,4-GL and its precursors, such as potassium hydrogen D-glucarate and calcium D-glucarate, may exert their anticancer action, in part, through alterations in steroidogenesis accompanied by changes in the hormonal environment and the proliferative status of the target organ. Thus, GA derivatives may be useful as new or adjuvant cancer preventive and therapeutic agents. In our study, 1,4-GL was found to be formed from the D-glucarate salt in the stomach of rats. It was apparently absorbed from the gastrointestinal tract, transported with the blood to different internal organs, and excreted in the urine and to a lesser extent in bile. There were no significant differences in the metabolism of PHG between male and female rats. Thus, formation of 1,4-GL from D-glucaric acid derivatives may be prerequisite for their inhibition of chemical carcinogenesis in rodents and prevention of breast, prostate, and colon cancer in humans.
Walaszek
Z
Z
University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, USA.
Szemraj
J
J
Narog
M
M
Adams
A K
AK
Kilgore
J
J
Sherman
U
U
Hanausek
M
M
D000818:Animals; D016588:Anticarcinogenic Agents / Q000493:pharmacokinetics*; D001646:Bile / Q000737:chemistry; D001711:Biotransformation; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D005937:Glucaric Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D005966:Glucuronidase / Q000037:antagonists & inhibitors; D007408:Intestinal Absorption; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014556:Urine / Q000737:chemistry
D016588:Anticarcinogenic Agents; C009194:saccharolactone; D005966:Glucuronidase; D005937:Glucaric Acid