Modulation of hepatic and renal drug metabolizing enzyme activities in rats by subchronic administration of farnesol.
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.
Horn
Thomas L
TL
Life Sciences Group, IIT Research Institute, Chicago, IL 60616, USA.
Long
Lina
L
Cwik
Michael J
MJ
Morrissey
Robert L
RL
Kapetanovic
Izet M
IM
McCormick
David L
DL
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005204:Farnesol / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D005204:Farnesol; D003577:Cytochrome P-450 Enzyme System; D016660:NAD(P)H Dehydrogenase (Quinone); D005980:Glutathione Reductase; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase