Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on heme oxygenase-1, biliverdin IXalpha reductase and delta-aminolevulinic acid synthetase 1 in rats with wild-type or variant AH receptor.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic accumulation of biliverdin and its monoglucuronide in moderately TCDD-resistant line B rats, but not in highly TCDD-resistant line A rats. In the mammalian heme degradation process, heme is cleaved to biliverdin by the rate-limiting enzyme heme oxygenase-1 (HO-1). Subsequently, biliverdin IXalpha reductase (BVRA) catalyzes the reduction of biliverdin to bilirubin. In heme biosynthesis, the rate-limiting enzyme is delta-aminolevulinic acid synthetase 1 (ALAS1). The effect of TCDD on HO-1, BVRA and ALAS1 was studied at the levels of mRNA (all three enzymes), protein expression (HO-1), and enzymatic activity (BVRA, liver only) in order to determine whether the accumulation of biliverdin could be due to their altered expression. In both lines A and B, 300 microg/kg TCDD transiently repressed hepatic HO-1 mRNA on day 2 but induced HO-1 protein expression at later time-points; however, the impact emerged earlier (day 14 vs. day 35) in line B rats. In spleen, TCDD repressed HO-1 mRNA and protein expression in lines A and B through days 2-35, but did not affect its mRNA levels in TCDD-sensitive L-E rats (10 days after 100 microg/kg). In all rat strains/lines, there was a strong repression of ALAS1 and a moderate induction of BVRA mRNA in liver, but mostly not in spleen. Hepatic BVRA activity was increased in lines A and B on day 14. At 5 weeks, it was still elevated in line A but reduced to 51% of control in line B. The results suggest that hepatic heme degradation is induced by TCDD in rats; however, this does not alone explain the accumulation of biliverdin in line B rats. Other factors such as the late repression of BVRA found here and possibly oxidative stress may be important contributors to biliverdin accumulation in these rats.
Niittynen
Marjo
M
Department of Environmental Health, National Public Health Institute, Box 95, FI-70701 Kuopio, Finland. marjo.niittynen@ktl.fi
Tuomisto
Jouni T
JT
Pohjanvirta
Raimo
R
D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis*; D000818:Animals; D001664:Biliverdine / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003001:Cloning, Molecular; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis; D005260:Female; D006418:Heme / Q000096:biosynthesis; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000096:biosynthesis*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D006418:Heme; D012313:RNA; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D051547:Heme Oxygenase-1; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D000624:5-Aminolevulinate Synthetase; D001664:Biliverdine