CHRONIC STRESS IMPAIRS OXIDATIVE-METABOLISM AND HEPATIC EXCRETION OF MODEL XENOBIOTIC SUBSTRATES IN THE RAT

Traumatic injury to both hard and soft tissue has been associated with a decrease in the rate of hepatic drug metabolism. The mechanism(s) underlying this phenomenon have yet to be determined, but may involve substances released from damaged tissues or activation of the adrenocortical axis secondary to stress. To determine whether a generalized stress response is involved in the trauma-induced perturbations of xenobiotic metabolism, rats were exposed to atraumatic stress for a period of 21 days prior to determining the disposition of antipyrine (an in vivo marker for the hepatic mixed-function oxidase system) and indocyanine green (a tricarbocyanine dye often used as an in vivo marker of active hepatic uptake). Exposure to stress resulted in a significant decrease in the systemic clearance of antipyrine, suggesting a stress-induced inhibition of hepatic oxidation. In addition, the stressed animals evidenced a decreased rate of uptake of indocyanine green by the liver, an apparent decrease in the storage of the dye within the liver, and a decreased hepatic clearance of indocyanine green (presumably due to a decrease in the K(M) for biliary transport). These observations suggest that atraumatic stress affects several processes involved in the hepatobiliary disposition of xenobiotics.