Toxicological Sciences, Vol 50, 10-19, Copyright © 1999 by Society of Toxicology
JM McKim Jr, S Choudhuri, PC Wilga, A Madan, LA Burns-Naas, RH Gallavan, RW Mast, DJ Naas, A Parkinson and RG Meeks
Decamethylcyclopentasiloxane (D5) is a cyclic siloxane with a wide range of
commercial applications. The present study was designed to investigate the
effects of D5 on the expression and activity of selected rat hepatic phase
I and phase II metabolizing enzymes. Female Fischer-344 rats were exposed
to 160 ppm D5 vapors (6 h/day, 7 days/week, for 28 days) by whole-body
inhalation. Changes in the activity and relative abundance of hepatic
microsomal cytochromes P450 (CYP1A, CYP2B, CYP3A, and CYP4A), epoxide
hydrolase, and UDP- glucuronosyltransferase (UDPGT) were measured. Repeated
inhalation exposure of rats to D5 increased liver size by 16% relative to
controls by day 28. During a 14-day post-exposure period, liver size in D5-
exposed animals showed significant recovery. Exposure to D5 did not change
total hepatic P450, but increased the activity of hepatic NADPH- cytochrome
c reductase by 1.4-fold. An evaluation of cytochrome P450 (CYP) enzymes in
hepatic microsomes prepared from D5-exposed rats revealed a slight
(1.8-fold) increase in 7-ethoxyresorufin O-deethylase (EROD) activity, but
no change in immunoreactive CYP1A1/2 protein. A moderate increase
(4.2-fold) in both 7-pentoxyresorufin O-depentylase (PROD) activity and
immunoreactive CYP2B1/2 protein (3.3-fold) was observed. Testosterone
6beta-hydroxylase activity was also increased (2.4-fold) as was CYP3A1/2
immunoreactive protein. Although a small increase in 11- and
12-hydroxylation of lauric acid was detected, no change in immunoreactive
CYP4A levels was measured. Liver microsomal epoxide hydrolase activity and
immunoreactive protein increased 1.7- and 1.4-fold, respectively, in the
D5-exposed group. UDPGT activity toward chloramphenicol was induced
1.8-fold, while no change in UDPGT activity toward 4-nitrophenol was seen.
These results suggest that the profile for enzyme induction following
inhalation exposure of female Fischer-344 rats to D5 vapors is similar to
that reported for phenobarbital, and therefore D5 may be described as a
weak "phenobarbital-like" inducer.
ARTICLES
Induction of hepatic xenobiotic metabolizing enzymes in female Fischer- 344 rats following repeated inhalation exposure to decamethylcyclopentasiloxane (D5)
Dow Corning Corporation, Health and Environmental Sciences, Midland, Michigan 48686, USA. james.m.mckim@am.pnu.com
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