Mechanism of cadmium-decreased glucuronidation in the rat.
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.
Alary
J
J
INSERM/INRA, Laboratoire des Xénobiotiques, Toulouse, France.
Cravedi
J P
JP
Baradat
M
M
Carrera
G
G
D000818:Animals; D002104:Cadmium / Q000494:pharmacology*; D002748:Chlorpropham / Q000031:analogs & derivatives / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003600:Cytosol / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism*; D005966:Glucuronidase / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009596:Nitrophenols / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014532:Uridine Diphosphate Glucose / Q000096:biosynthesis / Q000378:metabolism; D014535:Uridine Diphosphate Glucuronic Acid / Q000096:biosynthesis
D005965:Glucuronates; D009596:Nitrophenols; D002104:Cadmium; D002748:Chlorpropham; D009243:NAD; D014535:Uridine Diphosphate Glucuronic Acid; C078901:4-hydroxychlorpropham; D009249:NADP; D005966:Glucuronidase; D005947:Glucose; D014532:Uridine Diphosphate Glucose; C024836:4-nitrophenol