Farnesol demonstrates antitumor activity in several animal models for human
cancer and was being considered for development as a
cancer chemopreventive agent. This study was performed to characterize the effects of minimally toxic doses of
farnesol on the activity of phase I and II
drug metabolizing
enzymes. CD((R)) rats (20/sex/group) received daily gavage exposure to
farnesol doses of 0, 500, or 1000 mg/kg/day for 28 days; 10 rats/sex/group were necropsied at the termination of
farnesol exposure; remaining animals were necropsied after a 28-day recovery period. No deaths occurred during the study, and
farnesol had no significant effects on
body weight, food consumption, clinical signs, or hematology/coagulation parameters. Modest but statistically significant alterations in several clinical chemistry parameters were observed at the termination of
farnesol exposure; all clinical pathology effects were reversed during the recovery period. At the termination of dosing, the activities of CYP1A, CYP2A1-3,
CYP2B1/2, CYP2C11/12,
CYP2E1, CYP3A1/2, CYP4A1-3,
CYP19,
glutathione reductase,
NADPH/
quinone oxidoreductase and
UDP-glucuronosyltransferase were significantly increased in the livers of
farnesol-treated rats;
farnesol also increased the activity of
glutathione S-transferase in the kidney. The effects of
farnesol on hepatic and renal
enzymes were reversed during the recovery period. At the end of the dosing period, increases in absolute and relative liver and kidney weights were seen in
farnesol-treated rats. These increases may be secondary to induction of
drug metabolizing
enzymes, since organ weight increases were not associated with histopathologic alterations and were reversed upon discontinuation of
farnesol exposure. Administration of
farnesol at doses of up to 1000 mg/kg/day induced reversible increases in the activities of several hepatic and renal
drug metabolizing
enzymes in rats, while inducing only minimal toxicity. It is concluded that non-toxic or minimally toxic doses of
farnesol could alter the metabolism, efficacy, and/or toxicity of drugs with which it is co-administered.