Molecular and Cellular Endocrinology 190 (2002) 167 – 175 Vitamin A modulates the effects of thyroid hormone on UDP-glucuronosyltransferase expression and activity in rat liver Vale ´rie Haberkorn, Jean-Marie Heydel, Jacques Mounie, Yves Artur, Herve ´ Goudonnet * Unite ´ de Biochimie -Pharmacologie -Toxicologie, EA/MENRT 2980 UFR Pharmacie, Uniersite ´ de Bourgogne, 7 Bd. Jeanne d’Arc, BP 87900, 21079 Dijon, France Received 27 March 2001; accepted 24 September 2001 Abstract We studied the influence of thyroid hormones and vitamin A status on the regulation of UDP-glucuronosyltransferase (UGT) expression and the glucuronidation of thyroid hormones by UGTs. For this, we used an original model of rats fed with different vitamin A diets and implanted subcutaneously by osmotic minipumps delivering vehicle or thyroid hormones, which permitted the control of plasma thyroid hormone concentrations. The activity and expression of family 1 UGTs are correlated and were significantly modified by both thyroid status and amounts of retinol in the diet. Dietary vitamin A did not perturbe the UGT1A expression in thyroidectomized animals. Thyroid hormones and dietary vitamin A did not affect the activity and expression of family 2 UGTs. We conclude that thyroid hormones and vitamin A are co-regulator of the UGT1 family expression, without affecting the UGT2 family; by modifying activity and expression of the bilirubin UOT isoform, a member of UGT1 family, thyroid hormone reduced the glucuronidation of T4 and rT3. © 2002 Published by Elsevier Science Ireland Ltd. Keywords: UGT; Vitamin A; Thyroid hormones; Glucuronidation; Rat www.elsevier.com/locate/mce 1. Introduction The UDP-glucuronosyltransferases (UGTs, EC 2.4.1.17), a multigenic family of membrane-bound en- zymes, play a major role in detoxification and elimina- tion of endogenous substrates including bilirubin, bile acids, steroids, and thyroid hormones, and exogenous compounds like food additives, therapeutic drugs and environmental pollutants (Boutin et al., 1985; Siest et al., 1985; Mulder, 1986; Mackenzie et al., 1997). Based on nucleotide and amino acid sequence differences, mammalian UGTs can be grouped into two families of enzymes, respectively involved in the glucuronidation of different compounds. UGTs of family 1 derive from a single gene (Emi et al., 1995). This gene contains several alternative exons (exons 1), each of which encodes the amino-terminal domain specific to each form and has its own promoter. In addition four downstream exons (exons 2 – 5) encode the carboxy-terminal domain com- mon to all forms. The mRNAs encoding each form arise by differential splicing of each exon 1 to the common exon 2–5. Members of family 1 glucuronidate both planar and bulky phenols (UGT1A6, UGT1A7, UGT1A9) (Iyanagi et al., 1986; Harding et al., 1988), and bilirubin (UGT1A1, UGT1A2, UGT1A5 …) (Sato et al., 1990; Ritter et al., 1991). The second family, UGTs2, is responsible for steroid, bile acid and xenobi- otic glucuronidation (Radominska et al., 1994; Mackenzie et al., 1997); each of the isoforms of this family is encoded by a different gene. Besides other endogenous compounds, thyroid hor- mones are efficiently glucuronidated in hepatocytes by specific UGTs (Kostner et al., 1990; De Sandro et al., 1992; Visser et al., 1993a), and isoforms responsible for glucuronidation of these hormones have been identified (Visser et al., 1993b; Findlay et al., 2000). The predom- Abbreiations: UGT, UDP-glucuronosyltransferase; T3, 3,5,3-tri- iodo-L-thyronine; T4, 3,5,3,5-tetraiiodo-L-thyronine; rT3, 3,5,3-tri- iodo-L-thyronine; RT-PCR, reverse transcription-polymerase chain reaction; TR, thyroid hormone receptor; RAR, retinoic acid receptor; bp, base pair (s). * Corresponding author. Tel.: +33-3-80-393217; fax: +33-3-80- 393218. E-mail address: valeriehaberkorn@hotmail.com (V. Haberkorn). 0303-7207/02/$ - see front matter © 2002 Published by Elsevier Science Ireland Ltd. PII: S0303-7207(01)00681-5