Hepatic
necrosis produced by
carbon tetrachloride (0.02, 0.06, or 0.20 ml/kg, ip) in mice was found to be potentiated by simultaneous cotreatment with
phenylpropanolamine (200 mg/kg, ip), a
drug with
catecholamine-like pharmacologic effects. The ability to potentiate
carbon tetrachloride-induced hepatic
necrosis was shared by a compound with agonist effects relatively selective for alpha 2-adrenoreceptors (
clonidine, 5 mg/kg, ip), but not by specific alpha 1-adrenoreceptor agonists (
phenylephrine, up to 100 mg/kg, ip and
methoxamine, up to 50 mg/kg, ip) or by the beta-adrenoreceptor agonist
isoproterenol (up to 100 mg/kg, ip).
Yohimbine (5 mg/kg, ip), a selective alpha 2-adrenoreceptor antagonist, completely blocked the potentiating effect of
phenylpropanolamine on
carbon tetrachloride hepatotoxicity, providing further evidence that the increased hepatotoxic response with
phenylpropanolamine cotreatment was mediated through alpha 2-adrenoreceptor stimulation. Four potential mechanisms for
phenylpropanolamine potentiation of liver injury from
carbon tetrachloride were examined: (1) increased concentrations of
carbon tetrachloride in the liver from greater absorption or altered distribution; (2) diminished food consumption leading to a
starvation-like increase in responsiveness to
carbon tetrachloride; (3) impaired detoxification through a depletion of hepatic
glutathione content; and (4) enhanced toxicity produced by elevated core body temperature. None of these potential mechanisms was supported by the experimental results. It is concluded that
phenylpropanolamine and related compounds potentiate
carbon tetrachloride hepatotoxicity through a mechanism involving alpha 2-adrenoreceptor stimulation that has yet to be identified.