SEX-DIFFERENCES IN THE EXCRETION OF GLUCURONIDE CONJUGATES - THE ROLE OF INTRARENAL GLUCURONIDATION

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Abstract
Female Fischer 344 rats administered p-nitrophenol (0.05 mmol/kg) excrete more p-nitrophenylglucuronide in the urine than males (35.9 .+-. 2.9 vs. 14.1 .+-. 4.0% of total urinary metabolites, respectively). Hepatic microsomes prepared from male rats have higher UDP-glucuronyltransferase activity toward p-nitrophenol than hepatic microsomes from females (6.49 .+-. 0.67 vs. 3.20 .+-. 0.17 nmol/min per mg of protein, respectively). Sex differences in p-nitrophenylglucuronide excretion may be due to sex differences in either biliary excretion of glucuronide conjugate or in extrahepatic conjugation of p-nitrophenol. UDP-glucuronyltransferase activity in renal microsomes prepared from male and female rats toward p-nitrophenol was 0.21 .+-. 0.09 nmol/min per mg of protein and 0.91 .+-. 0.02 nmol/min per mg of protein, respectively. Vmax was greater in females than in males; Km was not sex linked. Similar in vitro sex differences were also observed with 1-naphthol as the aglycone. Renal microsomes prepared from male or female rats did not glucuronidate morphine. No sex differences in the excretion of morphine glucuronide were observed (16.4 .+-. 4.8 vs. 23.9 .+-. 5.3% of total urinary conjugates from males and females, respectively). Renal conjugation of p-nitrophenol in vivo was determined using the Specific Activity Difference Ratio technique. During infusion of 2 .mu.mol/min per kg of p-nitrophenol, 897.9 .+-. 26.0 nmol/min per kg of in vivo formed p-nitrophenylglucuronide was excreted in the urine of female rats whereas 715.6 .+-. 65.9 nmol/min per kg were excreted in males. Urinary excretion of p-nitrophenylglucuronide that was formed in the kidney was 198.9 .+-. 24.3 nmol/min per kg in female rats and 76.0 .+-. 28.2 nmol/min per kg in males rats. Biliary excretion of p-nitrophenylglucuronide represented approximately 6% of the administered dose and was not different between sexes. Renal UDP-glucuronyltransferase may contribute to the sex differences in p-nitrophenylglucuronide excretion.