Evidence for pteridine regulation of lead-mediated inhibition of uroporphyrinogen and heme formation in rat bone marrow.
Uroporphyrin I (URO I) accumulation has been reported in the bone marrow of rats exposed to lead, suggesting a sensitivity of uroporphyrinogen III cosynthase (COSYN) to this heavy metal. Furthermore, it has been reported that a polyglutamated folate derivative may serve as a coenzyme for the catalytic action of hepatic uroporphyrinogen III cosynthase. These findings raised the question of whether depletion of polyglutamated folate could enhance the susceptibility of bone marrow COSYN to lead and potentially interfere with the formation of heme. Nitrous oxide, an anesthetic agent capable of causing bone marrow tetrahydrofolate deficiency, depressed total bone marrow polyglutamated folate content by 42% with significant reductions in all three chain lengths (5-7) identified in the bone marrow during an exposure period of 7 days at 4 hr/day. Lead acetate (15 mg/kg) administered by ip injection at Days 0 and 2 during a 7-day exposure to nitrous oxide resulted in an 84% increase of bone marrow URO I content, which was markedly higher than the increases of 22 and 38% seen with sole administration of lead or nitrous oxide, respectively. The combination of agents also produced a 48% rise in COPRO I, a 39 and 43% decrease in COPRO III and protoporphyrin, respectively, and a 42% decline in the activity of microsomal 7-ethoxycoumarin O-deethylase, which is hemoprotein, cytochrome P-450 mediated. Heme oxygenase activity was not altered by nitrous oxide, lead, or their combination. These results suggest that bone marrow folate deficiency may render COSYN more sensitive to lead as characterized by increased uroporphyrin I and coproporphyrin I isomer content, decreased coproporphyrin III and protoporphyrin content, and depressed microsomal hemoprotein, cytochrome P-450-mediated drug-metabolizing capability.
Christenson
W R
WR
Department of Pharmacology, University of Nebraska Medical Center, Omaha 68105.
Bestervelt
L L
LL
Piper
W N
WN
D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004357:Drug Synergism; D006418:Heme / Q000096:biosynthesis*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007854:Lead / Q000633:toxicity*; D008297:Male; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D009609:Nitrous Oxide / Q000633:toxicity; D011524:Protoporphyrins / Q000096:biosynthesis / Q000302:isolation & purification; D011621:Pteridines / Q000378:metabolism*; D011624:Pteroylpolyglutamic Acids / Q000032:analysis / Q000172:deficiency*; D051381:Rats; D011919:Rats, Inbred Strains; D014576:Uroporphyrinogen III Synthetase / Q000378:metabolism; D014577:Uroporphyrinogens / Q000096:biosynthesis* / Q000302:isolation & purification
D011524:Protoporphyrins; D011621:Pteridines; D011624:Pteroylpolyglutamic Acids; D014577:Uroporphyrinogens; D007854:Lead; D006418:Heme; D015660:7-Alkoxycoumarin O-Dealkylase; D006419:Heme Oxygenase (Decyclizing); D014576:Uroporphyrinogen III Synthetase; D009609:Nitrous Oxide