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Partial beta‐oxidation and bilateral alpha‐oxidation of gamma‐hydroxybutyrate (GHB) in perfused rat livers
Author(s) -
ZHANG GuoFang,
Sadhukhan Sushabhan,
HAN Yong,
Tomcik Kristyen,
Murphy Anne,
Barnoff Stephanie,
Tochtrop Gregory,
Brunengraber Henri
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.504.4
Subject(s) - gamma hydroxybutyrate , formate , chemistry , alpha (finance) , citric acid cycle , biochemistry , metabolism , pharmacology , biology , medicine , catalysis , construct validity , patient satisfaction , nursing
GHB is neurotransmitter (GABA) and a drug of abuse. It is oxidized to succinate an intermediate of the citric acid cycle. We previously showed that GHB forms GHB‐CoA and 4‐phospho‐GHB‐CoA, an apparently dead‐end product (JBC, 2009). To investigate other fates of GHB, we perfused livers with unlabeled, [1,2‐ 13 C 2 ], [3,4‐ 13 C 2 ] or [ 13 C 4 ]GHB. No labeled acetyl‐CoA, acetoacetate or 3‐hydroxybutyrate were formed from the variously labeled GHB. So, there is no complete beta‐oxidation of GHB. We identified 4‐hydroxycrotonate which reflects an acyl‐CoA dehydrogenase reaction. Also, we found 3,4‐dihydroxybutyrate and 2,4‐dihydroxybutyrate which derive from two modes of hydration of the presumed 4‐hydroxycrotonyl‐CoA. The formation of 2,4‐dihydroxybutyrate was unexpected. Also, in livers perfused with [ 13 C 4 ]GHB, M3 4‐hydroxypropionate and M1 formate were formed. This suggests an alpha‐oxidation process. However, both [1,2‐ 13 C 2 ] and [3,4‐ 13 C 2 ]GHB formed small amounts of M1 formate, as well as M1 and M2 3‐hydroxypropionate. Thus, there must be two alpha‐oxidation processes in GHB oxidation (i) from 2,4‐dihydroxybutyryl‐CoA, and (ii) 3,4‐dihydroxybutyryl‐CoA presumably via 3‐hydroxybutanedioyl‐CoA (malyl‐CoA). Supported by NIDDK RoadMap and by NIEHS.