Effects of vasopressor hormones and modulators of protein kinase C on glutathione efflux from perfused rat liver.
Vasopressor hormones alter efflux of glutathione (GSH) and increase permeability of tight junctions in perfused rat liver. Infusions of 10 nM angiotensin II, 10 microM phenylephrine, and 10 nM vasopressin significantly increased efflux of GSH into perfusate by 32-41% and decreased biliary efflux by 31-57%. Direct modulation of protein kinase C (PKC) activity by 600 nM phorbol 12,13-dibutyrate (PDB), 5 microM 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), 5 microM sphingosine, or 10 nM staurosporine altered the pattern of efflux of GSH but not biliary oxidized glutathione disulfide (GSSG)-GSH ratios. Phorbol dibutyrate mimicked the vasopressor-mediated effects, increasing perfusate efflux by 31% and decreasing biliary efflux by 45%. Inhibitors of PKC caused qualitatively opposite responses, changing perfusate GSH by -37 to 18% and increasing biliary efflux by 22-161%. Whereas vasopressin increased penetration of [14C]sucrose into bile, modulation of PKC activity by PDB and H-7 did not affect the permeability of tight junctions to [14C]sucrose. Although pretreatment with H-7 blocked vasopressin-mediated changes in efflux of GSH, it did not prevent the increase in [14C]sucrose penetrance. We conclude that alterations in sinusoidal and biliary efflux of GSH can occur independent of changes in permeability of hepatocellular tight junctions. These findings suggest a role for protein kinase C in modulating the hepatic efflux of GSH.
Raiford
D S
DS
Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205.
Sciuto
A M
AM
Mitchell
M C
MC
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001646:Bile / Q000378:metabolism / Q000502:physiology; D000001:Calcimycin / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D007365:Intercellular Junctions / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013395:Sucrose / Q000493:pharmacokinetics; D014667:Vasopressins / Q000494:pharmacology*
D000963:Antimetabolites; D007555:Isoxazoles; D014667:Vasopressins; D010656:Phenylephrine; D015240:Phorbol 12,13-Dibutyrate; D000001:Calcimycin; D013395:Sucrose; D011493:Protein Kinase C; D005978:Glutathione; C006303:acivicin