Tertiary butyl alcohol in drinking water induces phase I and II liver enzymes with consequent effects on thyroid hormone homeostasis in the B6C3F1 female mouse.
Tertiary butyl alcohol (TBA) was administered to groups of 15 female B6C3F1 mice in drinking water at concentrations of 0, 2.0 or 20 mg TBA ml(-1), for 14 days, for assessment of gross and histological changes in the liver and thyroid, thyroid hormones (T3, T4, and TSH), total hepatic cytochrome P450 (Cyp) content, specific Cyp activities and quantitative PCR analysis of specific Cyp enzymes (Cyp1a1, Cyp2b9, Cyp2b10, Cyp3a11), sulfuryltransferases (ST1a1, ST2a2, and STn) and glucuronyltransferases (UGT1a1, UGT2b1, and UGT2b5). Phenobarbital (PB) was administered to a positive control group by oral gavage at a daily dose of 80 mg kg(-1). TBA caused, on day 14, a reduction in circulating T3 (12-15% decrease) and a dose-dependent reduction in T4 (13-22% decrease), with no evidence of thyroid pathology. Two of five livers examined in the 20 mg TBA ml(-1) dose group showed mild, diffuse centrilobular hypertrophy. On day 14, Cyp 7-benzoxyresorufin-O-debenzylase activity was significantly induced 12-fold by TBA at 20 mg ml(-1), and 1.8-fold at the 2.0 mg TBA ml(-1) concentration. Cyp 7-pentoxyresorufin-O-dealkylase activity was slightly induced (2.1-fold) by 20 mg TBA ml(-1) on day 14. Quantitative PCR analysis of gene transcripts showed a significant induction of Cyp2b10 and ST1a1 with both TBA concentrations, and a slight induction of Cyp2b9 at 20 mg TBA ml(-1) only. PB induced all phase I and phase II gene transcripts except for Cyp1a1 and Cyp2b9. These findings suggest that TBA, at and below doses used in chronic studies, is an inducer of phase I and phase II liver enzymes, with resulting decreases in circulating thyroid hormones in B6C3F1 mice.
Blanck
O
O
Bayer CropScience S.A., Sophia Antipolis, France.
Fowles
J
J
Schorsch
F
F
Pallen
C
C
Espinasse-Lormeau
H
H
Schulte-Koerne
E
E
Totis
M
M
Banton
M
M
D000428:Alcohol Drinking / Q000503:physiopathology; D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D006706:Homeostasis / Q000187:drug effects*; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008815:Mice, Inbred Strains; D010078:Oxazines / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D013961:Thyroid Gland / Q000187:drug effects; D013963:Thyroid Hormones / Q000494:pharmacology*; D013997:Time Factors; D014867:Water / Q000494:pharmacology*; D014881:Water Supply / Q000032:analysis; D020002:tert-Butyl Alcohol / Q000494:pharmacology*; D000099148:UGT1A1 Enzyme
D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D010078:Oxazines; D010634:Phenobarbital; D013963:Thyroid Hormones; D014867:Water; D020002:tert-Butyl Alcohol; D000099148:UGT1A1 Enzyme; C057754:benzyloxyresorufin