Hepatic glutathione suppression by the alpha-adrenoreceptor stimulating agents phenylephrine and clonidine.
The effects of alpha-adrenoreceptor stimulation on hepatic glutathione content were examined in ICR male mice using a selective alpha 1-adrenoreceptor stimulating agent, phenylephrine, and a selective alpha 2-adrenoreceptor stimulating drug, clonidine. Phenylephrine produced a dose-dependent depression in hepatic glutathione levels when administered by the intraperitoneal (i.p.) route, with a maximum extent of depression of approximately 30% occurring in both male and female mice. Phenylephrine was ineffective by the intracerebroventricular route, indicating a peripheral site of action which would be consistent with the mechanism(s) suggested by earlier in vitro studies using rat liver. Clonidine, an alpha 2-adrenoreceptor stimulating agent, also depressed hepatic glutathione concentrations in a dose-dependent manner. The maximum extent of depression (approx. 45%) from clonidine administered by the i.p. route was somewhat greater than that from phenylephrine, and the apparent potency was about 10-fold greater. Unlike phenylephrine, clonidine was effective when administered by the intracerebroventricular route. Pretreatment of mice with phenylephrine (100 mg/kg, i.p.) resulted in a potentiation of hepatic necrosis from a mildly hepatotoxic dose of acetaminophen (400 mg/kg, i.p.). The results of these experiments suggest that the changes in glutathione homeostasis produced by alpha-adrenoreceptor stimulation may be sufficient to impair detoxification mechanisms.
Center for Environmental and Human Toxicology, University of Florida, Gainesville.
R D
RD
Harbison
R C
RC
James
S M
SM
Roberts
D000082:Acetaminophen / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D003000:Clonidine / Q000494:pharmacology*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000187:drug effects* / Q000378:metabolism; D007276:Injections, Intraventricular; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D010656:Phenylephrine / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D010656:Phenylephrine; D000082:Acetaminophen; D005978:Glutathione; D003000:Clonidine