Induction of testosterone biotransformation enzymes following oral administration of methyl tert-butyl ether to male Sprague-Dawley rats.

Abstract

Methyl tert-butyl ether (MTBE) is an oxygenated fuel additive used to decrease carbon monoxide emissions during gasoline combustion. In the current study, we investigated the hypothesis that the MTBE-induced decrease in serum testosterone levels in male rats may be due in part to the ability of MTBE to induce the metabolism of endogenous testosterone and hence enhance its clearance. Nine-week-old male Sprague-Dawley rats were gavaged with 250, 500, 1000, or 1500 mg MTBE/kg/day in corn oil or corn oil alone for 15 or 28 consecutive days. Increased relative liver weight (10-14%) and minimal-to-moderate centrilobular hypertrophy were observed in rats treated with 1000 and 1500 mg MTBE/kg/day (high doses) for 28 days. Total hepatic microsomal cytochrome P450 (CYP) was increased 1. 3-fold in the high-dose, 15-day-treated rats. An evaluation of specific CYP activities using selective markers demonstrated a 2. 0-fold increase in CYP2B1/2 in rats treated with 1000 mg MTBE/kg/day for 28 days, and with 1500 mg MTBE/kg/day for 15 and 28 days (6.5- and 2.9-fold, respectively). CYP1A1/2, CYP2A1, and CYP2E1 activities were increased 1.5-, 2.4-, and 2.3-fold, respectively, in high-dose, 15-day-treated rats. CYP2E1 was also increased in high-dose, 28-day-treated rats (2.0-fold). CYP3A1/2 was increased 2.1-fold and UDP-glucuronosyltransferase activity 1.7-fold in high-dose, 28-day-treated rats. MTBE also induced its own metabolism 2.1-fold in high-dose, 28-day-treated rats. Results indicate that MTBE induces selected enzymes involved in testosterone metabolism. The decrease in serum testosterone observed following MTBE administration may be the result of enhanced testosterone metabolism and subsequent clearance.