Deconjugation of bilirubin-IX alpha glucuronides: a physiologic role of hepatic microsomal beta-glucuronidase.
beta-Glucuronidase is an acid hydrolase located in both the lysosomal and microsomal compartments of the hepatocyte. The function of the latter remains undefined. We postulated that microsomal beta-glucuronidase may be responsible for the deconjugation of bilirubin-IX alpha glucuronides which are synthesized primarily in the hepatic microsomal compartment. We utilized two unique congenic strains of mice to characterize the role of hepatic beta-glucuronidase in the metabolism and disposition of bilirubin-IX alpha; the first exhibited less than 1% of total hepatic beta-glucuronidase activity (ATM), the second lacked only the microsomal enzyme activity (AT1). The biliary excretion of bilirubin-IX alpha conjugates was quantitated using reverse-phase high performance liquid chromatography. Under basal conditions, there was a 2-fold increase in the biliary excretion of bilirubin-IX alpha monoglucuronides and total glucuronides in the AT1 and ATM mutants compared to the normal controls. When the plasma bilirubin-IX alpha level was increased to approximately 7 mg/dl to simulate hyperbilirubinemia, by intravenous administration of [14C]bilirubin-IX alpha, mathematical modeling of the biliary excretion curves of bilirubin-IX alpha glucuronides revealed qualitative differences between control and mutant animals, whereas both mutant groups were similar. Collectively, these data demonstrate that microsomal beta-glucuronidase modulates the net rate of bilirubin-IX alpha glucuronidation and glucuronide excretion in bile, under both basal and hyperbilirubinemic conditions, and that lysosomal beta-glucuronidase has no such effects. Hepatic microsomal beta-glucuronidase appears likely to influence the biliary excretion and hence the hepatic elimination of endogenous and xenobiotic substrates (e.g. carcinogens) which undergo hepatic glucuronidation.
Whiting
J F
JF
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Narciso
J P
JP
Chapman
V
V
Ransil
B J
BJ
Swank
R T
RT
Gollan
J L
JL
D000818:Animals; D001646:Bile / Q000378:metabolism; D001663:Bilirubin / Q000031:analogs & derivatives* / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism; D005966:Glucuronidase / Q000172:deficiency / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism*
D005965:Glucuronates; C016266:bilirubin glucuronate; D005966:Glucuronidase; D001663:Bilirubin