2,3,7,8-tetrachlorodibenzo-p-dioxin induces lecithin: retinol acyltransferase transcription in the rat kidney.
Vitamin A (retinoids) has an essential role in development and throughout life of humans and animals. Consequently, effects of the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on retinoid metabolism may be contributory to its toxicity. This study was performed to clarify the mechanism behind dioxin-induced retinyl ester formation in the rat kidney. In addition we investigated the possible role of CYP1A1 in dioxin-induced all-trans-retinoic acid (atRA) formation. Male Sprague-Dawley rats were exposed to a single oral dose of TCDD in a combined dose-response and time-course study, with doses ranging from 0.1 to 100 microg/kg bw and time points from 1 to 28 days. Levels of atRA and the expression of two potentially retinoic acid (RA)-controlled proteins critically involved in retinoid storage regulation, lecithin: retinol acyltransferase (LRAT) and cellular retinol binding protein I (CRBP I), were analyzed in liver and kidney. The expression and activity of cytochrome P4501A1 (assayed as ethoxyresorufin-O-deethylase activity) was assessed to gain insight into its potential role in RA synthesis. There was a significant increase in LRAT mRNA expression in the kidney, whereas no such increase could be observed in the liver, despite significantly increased atRA levels in both tissues. This suggests a tissue-specific regulation of LRAT by TCDD that may be dependent on other factors than atRA. Neither CRBP I mRNA nor protein levels were altered by TCDD. The time-course relationship between CYP1A1 activity and atRA levels in liver and kidney does not exclude a role of CYP1A1 in TCDD-induced RA synthesis. The observed altered regulation of the retinoid-metabolizing enzyme LRAT, together with the low doses and short time required by TCDD to change tissue RA levels, suggest that enzymes involved in retinoid metabolism are specific and/or direct targets of TCDD.
Hoegberg
Pi
P
Institute of Environmental Medicine, Karolinska Institutet, P.O Box 210, S-17177 Stockholm, Sweden.
Schmidt
Carsten K
CK
Nau
Heinz
H
Ross
A Catharine
AC
Zolfaghari
Reza
R
Fletcher
Nicholas
N
Trossvik
Christina
C
Nilsson
Charlotte B
CB
Håkansson
Helen
H
D000217:Acyltransferases / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D017931:DNA Primers; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D000217:Acyltransferases; C056942:lecithin-retinol acyltransferase