The effects of inhibition of haem biosynthesis by griseofulvin on intestinal iron absorption.
The relationship between haem biosynthesis and intestinal iron absorption in mice was investigated by ascertaining the effect of the haem synthesis inhibitor, griseofulvin, on duodenal iron absorption using both in vivo and in vitro measurements. Urinary 5-aminolaevulinic acid levels were increased within 24 hr of feeding mice with griseofulvin diet (2.5% w/w), with more marked increases seen after 3-7 days. Urinary porphobilinogen levels also showed a similar trend. In vivo intestinal iron absorption was significantly reduced (P<0.05) in experimental mice, mainly due to reduction in the transfer of 59Fe from the enterocytes to the portal circulation. In vitro studies using isolated duodenal fragments also exhibited marked decreases in both iron uptake and Fe (III) reduction. Changes in mucosal Divalent Metal Transporter 1 (DMT-1), Dcytb and Ireg1 (iron regulated protein 1) mRNA levels paralleled the changes in iron absorption. The reduction in iron absorption after griseofulvin treatment was normalised when mice were simultaneously injected with haem-arginate. These data support the hypothesis that intermediates in haem biosynthesis, particularly 5-aminolaevulinic acid, regulate intestinal iron absorption.
Laftah
Abas H
AH
Department of Clinical Biochemistry, GKT School of Medicine and Dentistry, Bessemer Rd, London SE5 9PJ, UK. abas.h.laftah@kcl.ac.uk
Raja
Kishor B
KB
Beaumont
Nick
N
Simpson
Robert J
RJ
Deacon
Allan
A
Solanky
Nita
N
Srai
Surjit Kaila S
SK
Peters
Timothy J
TJ
D000284:Administration, Oral; D000622:Aminolevulinic Acid / Q000652:urine; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D004347:Drug Interactions; D004386:Duodenum / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006118:Griseofulvin / Q000494:pharmacology*; D006418:Heme / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects*; D019266:Iron, Dietary / Q000493:pharmacokinetics*; D033862:Iron-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D011162:Porphobilinogen / Q000652:urine
D027682:Cation Transport Proteins; D019266:Iron, Dietary; D033862:Iron-Binding Proteins; D006118:Griseofulvin; D006418:Heme; D011162:Porphobilinogen; D000622:Aminolevulinic Acid