Dietary intake of S-(alpha-carboxybutyl)-DL-homocysteine induces hyperhomocysteinemia in rats.
Betaine homocysteine S-methyltransferase (BHMT) catalyzes the transfer of a methyl group from betaine to homocysteine (Hcy), forming dimethylglycine and methionine. We previously showed that inhibiting BHMT in mice by intraperitoneal injection of S-(alpha-carboxybutyl)-DL-homocysteine (CBHcy) results in hyperhomocysteinemia. In the present study, CBHcy was fed to rats to determine whether it could be absorbed and cause hyperhomocysteinemia as observed in the intraperitoneal administration of the compound in mice. We hypothesized that dietary administered CBHcy will be absorbed and will result in the inhibition of BHMT and cause hyperhomocysteinemia. Rats were meal-fed every 8 hours an L-amino acid-defined diet either containing or devoid of CBHcy (5 mg per meal) for 3 days. The treatment decreased liver BHMT activity by 90% and had no effect on methionine synthase, methylenetetrahydrofolate reductase, phosphatidylethanolamine N-methyltransferase, and CTP:phosphocholine cytidylyltransferase activities. In contrast, cystathionine beta-synthase activity and immunodetectable protein decreased (56% and 26%, respectively) and glycine N-methyltransferase activity increased (52%) in CBHcy-treated rats. Liver S-adenosylmethionine levels decreased by 25% in CBHcy-treated rats, and S-adenosylhomocysteine levels did not change. Furthermore, plasma choline decreased (22%) and plasma betaine increased (15-fold) in CBHcy-treated rats. The treatment had no effect on global DNA and CpG island methylation, liver histology, and plasma markers of liver damage. We conclude that CBHcy-mediated BHMT inhibition causes an elevation in total plasma Hcy that is not normalized by the folate-dependent conversion of Hcy to methionine. Furthermore, metabolic changes caused by BHMT inhibition affect cystathionine beta-synthase and glycine N-methyltransferase activities, which further deteriorate plasma Hcy levels.
Strakova
Jana
J
Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Williams
Kelly T
KT
Gupta
Sapna
S
Schalinske
Kevin L
KL
Kruger
Warren D
WD
Rozen
Rima
R
Jiracek
Jiri
J
Li
Lucas
L
Garrow
Timothy A
TA
D000596:Amino Acids / Q000032:analysis / Q000097:blood; D000818:Animals; D001622:Betaine / Q000097:blood; D050940:Betaine-Homocysteine S-Methyltransferase / Q000037:antagonists & inhibitors; D002794:Choline / Q000097:blood; D003541:Cystathionine beta-Synthase / Q000032:analysis / Q000378:metabolism; D004032:Diet; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D050938:Glycine N-Methyltransferase / Q000378:metabolism; D006710:Homocysteine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D020138:Hyperhomocysteinemia / Q000139:chemically induced* / Q000473:pathology; D008099:Liver / Q000737:chemistry / Q000201:enzymology / Q000473:pathology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012435:S-Adenosylhomocysteine / Q000032:analysis; D012436:S-Adenosylmethionine / Q000032:analysis
D000596:Amino Acids; D004791:Enzyme Inhibitors; D006710:Homocysteine; D001622:Betaine; D012436:S-Adenosylmethionine; C039751:5-(delta-carboxybutyl)homocysteine; D012435:S-Adenosylhomocysteine; D050938:Glycine N-Methyltransferase; D050940:Betaine-Homocysteine S-Methyltransferase; D003541:Cystathionine beta-Synthase; D002794:Choline
Hum Mutat. 2007 Sep;28(9):856-65
17436311
Biochem Biophys Res Commun. 1982 Sep 16;108(1):344-8
7150291
Annu Rev Nutr. 1999;19:217-46
10448523
J Nutr. 1986 Jun;116(6):985-90
3088229
N Engl J Med. 2002 Feb 14;346(7):476-83
11844848
Hum Mol Genet. 2005 Aug 1;14(15):2201-8
15972722
J Biol Chem. 1998 Oct 16;273(42):27043-6
9765216
J Biochem. 1981 Dec;90(6):1603-10
7333998
Am J Physiol Regul Integr Comp Physiol. 2004 Jul;287(1):R39-46
15016621
Physiol Rev. 1992 Jan;72(1):101-63
1731369
J Biol Chem. 1987 Feb 25;262(6):2485-93
3818603
Am J Med Genet A. 2003 Jun 1;119A(2):172-6
12749058
J Biol Chem. 1984 Aug 10;259(15):9508-13
6746658
Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6489-94
16614071
J Hypertens. 2006 Aug;24(8):1499-505
16877951
Thromb Haemost. 2010 Aug;104(2):231-42
20458436
Am J Clin Nutr. 2006 Jan;83(1):5-10
16400042
J Nutr. 1993 Nov;123(11):1939-51
8229312
Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1585-9
7878023
J Nutr. 2004 Nov;134(11):2913-8
15514252
Lancet. 1995 Jan 21;345(8943):149-51
7741859
N Engl J Med. 1991 Jan 17;324(3):199-200
1984202
Arch Biochem Biophys. 2001 Sep 1;393(1):184-6
11516176
Clin Sci (Lond). 1991 Oct;81(4):551-6
1657504
Hypertens Res. 2001 Jul;24(4):453-7
11510759
Clin Chem. 2003 Feb;49(2):286-94
12560353
J Nutr. 2003 Nov;133(11):3392-8
14608049
J Nutr. 1983 Mar;113(3):519-21
6827372
Atherosclerosis. 2005 Jul;181(1):159-65
15939068
Methods Enzymol. 1981;71 Pt C:576-81
6268934
Mol Genet Metab. 2007 May;91(1):104-10
17376725
Atherosclerosis. 2010 Jan;208(1):19-25
19592001
Proc Natl Acad Sci U S A. 1984 Jun;81(12):3631-4
6587377
J Biol Chem. 2003 Jun 13;278(24):21851-9
12668679
N Engl J Med. 1991 Apr 25;324(17):1149-55
2011158
Hum Mol Genet. 2001 Mar 1;10(5):433-43
11181567
J Biol Chem. 1999 Mar 19;274(12):7816-24
10075673
Biochem Biophys Res Commun. 1999 Sep 7;262(3):624-8
10471374
Behav Res Methods. 2007 May;39(2):175-91
17695343
Methods Enzymol. 2007;428:439-58
17875433
Proc Natl Acad Sci U S A. 2001 May 8;98(10):5560-5
11320206
Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):12880-5
9371769
Cancer Res. 1989 Aug 1;49(15):4094-7
2743304
Circ Res. 2004 May 28;94(10):1318-24
15105297
J Intern Med. 1999 Nov;246(5):425-54
10583714
J Biol Chem. 2003 Feb 21;278(8):5952-5
12482759
J Med Chem. 2006 Jun 29;49(13):3982-9
16789755
J Nutr. 2006 Jun;136(6):1493-7
16702310
J Nutr. 1982 Dec;112(12):2217-26
7143104
J Physiol. 2009 Aug 15;587(Pt 16):4001-13
19564394
Atherosclerosis. 2003 Apr;167(2):205-14
12818402
Methods Enzymol. 1992;209:366-74
1495417
Mol Genet Metab. 2000 Nov;71(3):511-9
11073719