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Biochem Pharmacol ; 44(11): 2139-47, 1992 Dec 01.
Article in English | MEDLINE | ID: mdl-1472079

ABSTRACT

In isolated rat hepatocytes, cadmium (0-200 microM) decreased the overall glucuronidation of both isopropyl N-(3-chloro-4 hydroxyphenyl)carbamate (4-hydroxychlorpropham, 4-OHCIPC) and 4-nitrophenol in a concentration-dependent manner. In contrast, in native rat liver microsomes, glucuronidation of 4-OHCIPC was increased by cadmium through activation of microsomal 4-OHCIPC glucuronosyl transferase. In addition, in rat microsome incubations, the net amount of 4-OHCIPC glucuronide was also indirectly increased by cadmium through a reduction in the activity of beta-glucuronidase. As the effect of cadmium on the activity of 4-OHCIPC glucuronosyl transferase could not account for the decrease in glucuronide formation in intact hepatocytes, the influence of cadmium on the availability of UDP-glucuronic acid (UDPGA) was investigated further. In isolated rat hepatocytes, cadmium depleted the UDPGA content in a dose-dependent manner without a change in the UDP glucose (UDPG) content. Cadmium did not increase the breakdown of UDPGA by microsomal UDPGA pyrophosphatase but strongly decreased (30-66%) the synthesis of the cofactor in the cytosol by inhibiting UDP-glucose dehydrogenase (UDPGDH). Cadmium (10-50 microM) was found to inhibit the purified enzyme from bovine liver (EC 1.1.1.22) non-competitively. In vivo in the absence of a substrate undergoing glucuronidation, cadmium administration, 1.5 and 2.5 mg Cd/kg i.v., to normally fed rats resulted in a 15 and 30% decrease of hepatic UDPGA, respectively. However, in the liver, neither the NAD+/NADH ratio nor the UDPG content was significantly changed following cadmium treatment. Both in vitro and in vivo results support the conclusion that in intact cells the reduction in overall 4-OHCIPC glucuronidation caused by cadmium was due to a decrease in UDPGA availability which results from the inhibiting effect of cadmium on UDPGDH.


Subject(s)
Cadmium/pharmacology , Glucuronates/metabolism , Liver/drug effects , Animals , Chlorpropham/analogs & derivatives , Chlorpropham/metabolism , Chromatography, High Pressure Liquid/methods , Cytosol/metabolism , Glucose/metabolism , Glucuronidase/drug effects , Glucuronidase/metabolism , Liver/enzymology , Liver/metabolism , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , NAD/metabolism , NADP/metabolism , Nitrophenols/metabolism , Rats , Rats, Sprague-Dawley , Uridine Diphosphate Glucose/biosynthesis , Uridine Diphosphate Glucose/metabolism , Uridine Diphosphate Glucuronic Acid/biosynthesis
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