Hepatic subcellular distribution of manganese in manganese and manganese-bilirubin induced cholestasis.
Administration of non-cholestatic doses of manganese (Mn2+) followed by injection of bilirubin (BR) results in a severe reduction in rat bile flow. Male Sprague-Dawley rats were given various doses of Mn2+ (2, 4.5, 8, and 18 mg/kg, i.v.) and killed 0.25, 1, 3, or 5 hr later. 54Mn2+ was used to evaluate Mn2+ content (micrograms/g protein) in different liver fractions: homogenate, mitochondria, microsomes, cytoplasm, nuclei-membrane fraction and liver cell plasma membrane fractions, one containing bile canalicular complexes (LCPM-BCM), the other containing sinusoidal membranes (LCPM-PM). In LCPM-BCM and LCPM-PM, two time-related patterns of Mn2+ content were observed. With non-cholestatic doses (2, 4.5, and 8 mg/kg), Mn2+ content decreased with time and rarely exceeded 50 micrograms/g protein. With 18 mg/kg (a cholestatic dose), Mn2+ content increased with time and reached values over 100 micrograms/g protein (3-5 hr), reflecting possible modification in membrane structure. BR caused a marked increase in Mn2+ content (at a dose of 4.5 mg Mn2+/kg) in LCPM-BCM (240%), approaching values seen with 18 mg Mn2+/kg, whereas in LCPM-PM it was less striking (50%). These and other results obtained with various treatments (cholestatic and non-cholestatic) suggest than Mn2+ concentration in bile canalicular membranes is a critical factor in both forms of cholestasis, and that BR can facilitate Mn2+ incorporation in the bile canalicular membrane.
D000818:Animals; D001663:Bilirubin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002779:Cholestasis / Q000139:chemically induced* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008345:Manganese / Q000378:metabolism*; D020149:Manganese Poisoning; D051381:Rats; D011919:Rats, Inbred Strains; D013448:Sulfobromophthalein / Q000494:pharmacology; D013997:Time Factors
D013448:Sulfobromophthalein; D008345:Manganese; D001663:Bilirubin; D002118:Calcium