PMID- 8921345
OWN - NLM
STAT- MEDLINE
DCOM- 19970304
LR  - 20190909
IS  - 0272-0590 (Print)
IS  - 0272-0590 (Linking)
VI  - 33
IP  - 2
DP  - 1996 Oct
TI  - Retinoid-induced hypertriglyceridemia in rats is mediated by retinoic acid 
      receptors.
PG  - 264-71
AB  - Retinoids in clinical use today are known to induce hypertriglyceridemia as one 
      of their major side effects. The purpose of the present study was to determine, 
      in an appropriate animal model, if retinoid-induced hypertriglyceridemia is 
      mediated by retinoic acid receptors (RARs) and/or by retinoid X receptors (RXRs). 
      Oral gavage of male Fischer rats with 13-cis-retinoic acid for 6 days caused a 
      rapid and sustained increase in serum triglycerides that was reversible within 4 
      days posttreatment. In subsequent experiments, rats were treated by gavage once 
      daily for 3 days with various retinoids, and serum triglyceride levels were 
      determined 24 hr after the last treatment without fasting. All-trans- and 
      13-cis-retinoic acid, which can be converted to both RAR and RXR agonists, and 
      9-cis-retinoic acid, an RAR/RXR pan-agonist, caused dose-dependent increases in 
      serum triglycerides at doses that did not cause weight loss or mucocutaneous 
      toxicity. Ro 13-6298 and AGN 190121, two RAR-specific agonists, caused 
      dose-dependent increases in serum triglycerides, although Ro 13-6298 only induced 
      hypertriglyceridemia at weight-suppressive doses. Two RXR-selective agonists, 
      LG100268 and AGN 191701, failed to induce hypertriglyceridemia or weight loss up 
      to the highest doses tested. A structural isomer of AGN 190121 that does not 
      activate RARs or RXRs, AGN 190727, did not induce hypertriglyceridemia. 
      Hypertriglyceridemia induced by AGN 190121 was significantly inhibited by 
      cotreatment with an RAR-selective antagonist, AGN 193109. Taken together, these 
      data provide strong evidence that retinoid-induced hypertriglyceridemia is 
      mediated, at least in part, by RARs. These data also suggest that RXR-specific 
      agonists may have reduced potential to induce hypertriglyceridemia relative to 
      RAR-active retinoids.
FAU - Standeven, A M
AU  - Standeven AM
AD  - Department of Biology, Allergan Inc., Irvine, California 92713-9534, USA.
FAU - Beard, R L
AU  - Beard RL
FAU - Johnson, A T
AU  - Johnson AT
FAU - Boehm, M F
AU  - Boehm MF
FAU - Escobar, M
AU  - Escobar M
FAU - Heyman, R A
AU  - Heyman RA
FAU - Chandraratna, R A
AU  - Chandraratna RA
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Fundam Appl Toxicol
JT  - Fundamental and applied toxicology : official journal of the Society of 
      Toxicology
JID - 8200838
RN  - 0 (AGN 190727)
RN  - 0 (Naphthalenes)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoids)
RN  - EH28UP18IF (Isotretinoin)
RN  - ZC6062V1O9 (AGN 193109)
SB  - IM
MH  - Animals
MH  - Fasting
MH  - Hypertriglyceridemia/*chemically induced
MH  - Isotretinoin/*toxicity
MH  - Male
MH  - Naphthalenes/pharmacology
MH  - Rats
MH  - Rats, Inbred F344
MH  - Receptors, Retinoic Acid/antagonists & inhibitors/physiology
MH  - Retinoids/pharmacology
EDAT- 1996/10/01 00:00
MHDA- 1996/10/01 00:01
CRDT- 1996/10/01 00:00
PHST- 1996/10/01 00:00 [pubmed]
PHST- 1996/10/01 00:01 [medline]
PHST- 1996/10/01 00:00 [entrez]
AID - S0272059096901645 [pii]
AID - 10.1006/faat.1996.0164 [doi]
PST - ppublish
SO  - Fundam Appl Toxicol. 1996 Oct;33(2):264-71. doi: 10.1006/faat.1996.0164.