Tm. Williams et Sj. Borghoff, Induction of testosterone biotransformation enzymes following oral administration of methyl tert-butyl ether to male Sprague-Dawley rats, TOXICOL SCI, 57(1), 2000, pp. 147-155
Methyl tert-butyl ether (MTBE) is an oxygenated fuel additive used to decre
ase carbon monoxide emissions during gasoline combustion. In the current st
udy, 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, 50
0, 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-m
oderate centrilobular hypertrophy were observed in rats treated with 1000 a
nd 1500 mg MTBE/kg/day (high doses) for 28 days. Total hepatic microsomal c
ytochrome P450 (CYP) was increased 1.3-fold in the high-dose, 15-day-treate
d rats. An evaluation of specific CYP activities using selective markers de
monstrated a 2.0-fold increase in CYP2B1/2 in rats treated with 1000 mg MTB
E/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-trea
ted 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 acti
vity 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 tha
t MTBE induces selected enzymes involved in testosterone metabolism. The de
crease in serum testosterone observed following MTBE administration may be
the result of enhanced testosterone metabolism and subsequent clearance.