ABSTRACT
Toxoplasma gondii infection in marine mammals is intriguing and indicative of contamination of the ocean environment and coastal waters with oocysts. Toxoplasma gondii infection was detected in captive marine mammals at a sea aquarium in Canada. Antibodies to T. gondii were found in all 7 bottlenose dolphins (Tursiops truncatus) tested. Two of these dolphins, as well as a walrus (Odobenus rosmarus) at the facility, died. Encephalitis and T. gondii tissue cysts were identified in histological sections of the brain of 1 dolphin (dolphin no. 1). Another dolphin (dolphin no. 2) had mild focal encephalitis without visible organisms, but viable T. gondii was isolated by bioassay in mice and cats from its brain and skeletal muscle; this strain was designated TgDoCA1. The PCR-RFLP typing using 11 markers (B1, SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico) identified a Type II strain. The DNA sequencing of B1 and SAG1 alleles amplified from TgDoCA1 and directly from the brains of dolphin no. 1 and the walrus showed archetypal alleles consistent with infection by a Type II strain. No unique polymorphisms were detected. This is apparently the first report of isolation of T. gondii from a marine mammal in Canada.
Subject(s)
Bottle-Nosed Dolphin/parasitology , Toxoplasmosis, Animal/epidemiology , Toxoplasmosis, Cerebral/veterinary , Walruses/parasitology , Animals , Animals, Zoo , Antibodies, Protozoan/blood , Biological Assay/veterinary , Brain/parasitology , Brain/pathology , Canada/epidemiology , Cats , DNA, Protozoan/analysis , DNA, Protozoan/chemistry , Female , Immunohistochemistry/veterinary , Male , Mice , Polymerase Chain Reaction/veterinary , Polymorphism, Restriction Fragment Length , Toxoplasma/classification , Toxoplasma/genetics , Toxoplasma/immunology , Toxoplasma/isolation & purification , Toxoplasmosis, Animal/diagnosis , Toxoplasmosis, Animal/parasitology , Toxoplasmosis, Cerebral/diagnosis , Toxoplasmosis, Cerebral/epidemiology , Toxoplasmosis, Cerebral/parasitologySubject(s)
ATP-Binding Cassette Transporters , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Carrier Proteins/pharmacology , Flavonoids/adverse effects , Flavonoids/pharmacokinetics , Hyperbilirubinemia/chemically induced , Piperidines/adverse effects , Piperidines/pharmacokinetics , Animals , Antineoplastic Agents/metabolism , Disease Models, Animal , Drug Interactions , Flavonoids/metabolism , Hyperbilirubinemia/physiopathology , Male , Piperidines/metabolism , Rats , Rats, WistarABSTRACT
Flavopiridol (FLAP) is a novel anticancer agent that is extensively glucuronidated in patients. Biliary excretion is the main elimination pathway of FLAP conjugates responsible for enterohepatic recirculation and for the main side effect diarrhea. To investigate the hepatic transport system for FLAP glucuronides, livers of Wistar and Mrp2-deficient TR- rats were perfused with FLAP (30 microM) in a single pass system. Biliary excretion and efflux into perfusate during a 60 min period greatly differ in TR- rats. While cumulative biliary excretion of M1 and M2 was significantly reduced to 4.3% and 5.4% efflux into perfusate was increased by 1.5 and 4.2-fold. This indicates that in control rats, M1 and M2 are almost exclusively eliminated into bile by Mrp2. Cumulative FLAP secretion into bile and perfusate, however, was non-significantly reduced by 36.7% and 43.2% in the mutant rat strain, suggesting that besides Mrp2, other transporters might also be involved in FLAP elimination. FLAP stimulates bile flow up to 24% in control rats, but secretion is nearly absent in TR- rats further supporting an efficient transport of FLAP glucuronides by Mrp2. FLAP (30 microM) also reversibly inhibited the Mrp2-mediated biliary elimination of bilirubin and bromsulphthalein in Wistar rats by 54% and 51%, respectively, indicating a competition with the elimination of Mrp2-specific substrates. In summary, we found that FLAP glucuronides are substrates of Mrp2 effectively inhibiting the biliary excretion of bilirubin. This may explain the increased serum bilirubin levels observed in cancer patients during FLAP therapy.
