Potentiation of carbon tetrachloride hepatotoxicity by phenylpropanolamine

Abstract

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 α 2-adrenoreceptors (clonidine, 5 mg/kg, ip), but not by specific α 1-adrenoreceptor agonists (phenylephrine, up to 100 mg/kg, ip and methoxamine, up to 50 mg/kg, ip) or by the β-adrenoreceptor agonist isoproterenol (up to 100 mg/kg, ip). Yohimbine (5 mg/kg, ip), a selective α 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 α 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 α 2-adrenoreceptor stimulation that has yet to be identified.