Altered hepatic functions and microsomal activity in perfused rat liver by hyperthermia combined with alkylating...

Livers of fasted rats were perfused for one hour in the presence of cyclophosphamide (CP), mechlorethamine (HN2), or melphalan (L-PAM) at 37 degrees and 42 degrees C. Hepatic biosynthetic function was assessed by determining gluconeogenesis from lactate, ureogenesis from NH4Cl, and O2 consumption. Antipyrine (AP) metabolism was employed to assess microsomal mixed function oxygenase enzyme activity at elevated temperatures. The t 1/2 of AP increased 2.8-fold in a temperature-dependent manner between 37 degrees and 43 degrees C. In the presence of biosynthetic substrates, the t 1/2 of AP increased 1.8-fold between 37 degrees and 43 degrees C. CP activation was suppressed (27% at 125 micrograms/ml, 49% at 500 micrograms/ml) at 42 degrees C. The presence of biosynthetic substrates significantly attenuated the suppression of CP activation by hyperthermia. A dose-dependent decrease in biosynthetic function occurred in the presence of CP at 37 degrees and 42 degrees C suggesting hepatotoxicity and/or competition for biochemical intermediates. The t 1/2 of HN2 at 50 micrograms/ml was slightly decreased by 11% at 42 degrees C (19.6 min vs. 17.4 min). The half-lives of 10 micrograms/ml HN2 and 5 micrograms/ml L-PAM were not altered at 42 degrees C (17.1 min vs. 16.4 min and 44.6 min vs. 44.1 min, respectively). The adverse effects of HN2 and L-PAM on hepatic biosynthetic functions were minimal suggesting that alkylating agents not requiring metabolism by the liver would be most useful for hepatic thermochemotherapy. The data indicate that hyperthermia depresses hepatic microsomal drug metabolizing enzyme function and alters the perfusate pharmacokinetics of alkylating agents. Moreover, manipulation of the hepatic biochemical environment may modify the adverse effects of hyperthermia on microsomal activity.