Liquid-Chromatographic Methods for Carboxylic Acids

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1		Makoto Tsunoda	+ 1634 word(s)	1634	2020-11-23 05:17:15

This entry is adapted from the peer-reviewed paper 10.3390/molecules25214883

Carboxyl-bearing low-molecular-weight compounds such as keto acids, fatty acids, and other organic acids are involved in a myriad of metabolic pathways owing to their high polarity and solubility in biological fluids. Various disease areas such as cancer, myeloid leukemia, heart disease, liver disease, and lifestyle diseases (obesity and diabetes) were found to be related to certain metabolic pathways and changes in the concentrations of the compounds involved in those pathways. Therefore, the quantification of such compounds provides useful information pertaining to diagnosis, pathological conditions, and disease mechanisms, spurring the development of numerous analytical methods for this purpose.

fluorescence mass spectrometry fatty acids perfluorinated carboxylic acids α-keto acids

1. Introduction

Quantification of low-molecular-weight compounds, as exemplified by metabolomics studies, has become increasingly important in the life sciences. Metabolite analysis provides metabolic and biochemical status of particular biological systems and valuable insights into disease development and diagnosis ^[1]^[2]^[3]^[4]^[5]^[6]. There are numerous classes of low-molecular-weight compounds, and they are categorized based on their functional groups, including amine, thiol, and carboxylic groups. Low-molecular-weight carboxylic acids are involved in various metabolic pathways. For example, the tricarboxylic acid (TCA) cycle, which is the principal energy-producing process in cells, involves nine carboxylic acid compounds. Fatty acids are integral components of lipids, and consist of carboxylic acids with long aliphatic chains.

Hence, highly sensitive and selective methods for the determination of biologically important carboxylic acids are required for biological investigations, and, thus far, numerous analytical methods have been developed. For selective determination, solid-phase extraction or solvent extraction pretreatment is commonly performed, followed by separation techniques such as liquid chromatography (LC), gas chromatography (GC), and capillary electrophoresis. The choice of detection method is important for trace amounts of carboxylic acids in biological samples. Ultraviolet absorbance detection is rarely implemented due to the absence of chromophores in carboxylic acids. Fluorescence detection following derivatization and mass spectrometry has the advantage of high sensitivity.

2. Analytical methods for fatty acids in biological samples

Target Compounds

Biological Sample

Sample Treatment

Derivatization Reagent

Separation Mode

Detection Method

LOD

Recovery

Ref.

7 Fatty acids

Human serum

Acid extraction

APF

RPLC

FL: 467/512 nm

0.1–6.4 nM

93–105%

^[7]

3 Fatty acids

Human plasma

Acid extraction

NOEPES

RPLC

FL: 235/366 nm

56 fmol

–

^[8]

6 Fatty acids

Human plasma

Acid extraction

HEC

RPLC

FL: 293/365 nm

38–57 fmol

102–106%

^[9]

6 Fatty acids

Human plasma

Acid extraction

HEC

RPLC

FL: 335/365 nm

45–68 fmol

102–105%

^[10]

5 Fatty acids

Human serum

Acid extraction

DBD-ED

RPLC

FL: 450/560 nm

2.29–4.75 fmol

108–113%

^[11]

8 Fatty acids

Rat plasma

Acid extraction

DBD-ED

RPLC

FL: 450/560 nm

–

^[12]

4 Epoxyeicosatrienoic acids

Bovine endothelial cells

Solid phase extraction

RPLC

FL: 259/395 nm

<2 pg

83–89%

^[13]

25 Fatty acids

Mouse serum

Acid extraction

AMPP

RPLC

MS/MS

50–100 fg (LOQ)

–

^[14]

11 Fatty acids

Mouse serum, bronchial epithelial cells

Solid phase extraction

AMPP

RPLC

MS/MS

200–900 fg (LOQ)

–

^[15]

20 Fatty acids

Breast cancer cells

Solvent extraction

Aminoxy

TMT

RPLC

MS/MS

40 fmol

–

^[16]

8 Fatty acids

Rat plasma

Acid extraction

DBD-PZ-NH₂

RPLC

<0.1 µM

–

^[17]

9 Fatty acids

Rat plasma

Solvent extraction

DAABD-AE

RPLC

6.5–21 fmol

–

^[18]

MePZBD-AE

RPLC

8.8–32 fmol

–

^[18]

APZBD-NHMe

RPLC

35–150 fmol

–

^[18]

56 Fatty acids

Human plasma

Centrifugation

Choline

HILIC

50 ng/mL

–

^[19]

38 Fatty acids, acylcarnitines

Human plasma

Centrifugation

Dansyl-hydrazine

RPLC

MS/MS

76–152 pM

–

^[20]

18 Fatty acids

Human urine

Solid phase extraction

d₀-DMPP,

d₆-DMPP

RPLC

MS/MS

5–15 pM

–

^[21]

60 Fatty acids

Human serum

Acid extraction

DMED, d₄-DMED

RPLC

–

^[22]

6 Fatty acids

Human blood

Acid extraction

None

RPLC

low pg range

–

^[23]

4 Fatty acids

Human serum, plasma

Solvent extraction

None

RPLC

ECD

50 pmol

92–102%

^[24]

6 Fatty acids

Human plasma

Solvent extraction

None

RPLC

ECD

50 pmol

92–102%

^[25]

11 Fatty acids

Human plasma

Solvent extraction

AEMP, NAPP

RPLC

Electrogenerated chemilu minescence

70 fmol

–

^[26]

APF: 6-oxy-(acetyl piperazine)fluorescein, NOEPES: 2-(2-naphoxy)ethyl 2-(piperidino)ethanesulfonate, HEC: 9-(2-hydroxyethyl)-carbazole, DBD-ED: 4-N,N-dimethylaminosulfonyl-7-N-(2-aminoethyl)amino-2,1,3-benzoxadiazole, NT: 2-(2,3-naphthalimino)ethyl trifluoromethanesulfonate, AMPP: N-(4-aminomethylphenyl)pyridinium, AminoxyTMT: aminoxy tandem mass tags, DBD-PZ-NH₂: 7-(N,N-dimethylaminosulfonyl)-4-(aminoethyl)piperazino-2,1,3-benzoxadiazole, DAABD-AE: 4-[2-(N,N-dimethylamino)ethylaminosulfonyl]-7-(2-aminoethylamino)-2,1,3-benzoxadiazole, MePZBD-AE: [4-(4-N-methyl)piperazinosulfonyl]-7-(2-aminoethylamino)-2,1,3-benzoxadiazole, APZBD-NHMe: [4-(4-N-aminoethyl)piperazinosulfonyl]-7-methylamino-2,1,3-benzoxadiazole, DMPP: 2,4-dimethoxy-6-piperazin-1-yl pyrimidine, DMED: 2-dimethylaminoethylamine, AEMP: 2-(2-aminoethyl)-1-methylpyrrolidine, NAPP: N-(3-aminopropyl)pyrrolidine.

3. Analytical methods for TCA cycle and glycolysis-related compounds in biological samples

Target Compounds	Biological Sample	Sample Treatment	Derivatization Reagent			Separation Mode	Detection Method	LOD	Recovery	Ref.
Fumaric acid	Rat liver, spleen and urine	Centrifugation			None	RPLC	PDA: 215 nm	0.01 µg	89–92%	^[27]
Maleic acid	Rat serum and urine	Centrifugation			None	RPLC	MS/MS	0.2 µg/L	94–111%	^[28]
Methylma-lonic acid	Human plasma	Centrifugation			None	HILIC	MS	0.03 µM	90–93%	^[29]
Lactic acid	Human urine and saliva	Centrifugation			9-CMA	RPLC	UV: 365 nm, FL: 365/410 nm	50 nM	92–106%	^[30]
Oxalic acid	Mouse urine and hepatocyte	Centrifugation			None	Ion exclu sion chrom atography	MS/MS	2 µM	–	^[31]
6 TCA metabolites	Rat urine	Centrifugation			DBD-PZ	RPLC	FL: 450/560 nm	2–15 fmol	80–96%	^[32]
9 Organic acids	Yeast	Centrifugation		None		Ion exclu sion chrom atography	UV: 210 nm	0.6–29.3 mg/L	98–103%	^[33]
32 Organic acids	Human urine	Solvent extraction		None		Ion exclu sion chrom atography	UV: 220 nm	0.002–2.2 mg/L	–	^[34]
13 Organic acids	Mouse urine	Centrifugation		1-Pyrene methylamine		RPLC	FL: 345/375, 345/475 nm	4–22 fmol	–	^[35]
30 Organic acids	Mouse ser um, urine, and tissue	Centrifugation		None		HILIC, Ion pair RPLC	MS/MS	<5 µM	–	^[36]
59 Organic acids	Human melanoma cells	Centrifugation		Phenylh-drazine		Ion pair RPLC	MS	–	–	^[37]
138 Organic acids	Yeast	Centrifugation		None		RPLC	MS/MS	0.001–3.7 µM	–	^[38]
TCA metabolites	Human red blood cell	Centrifugation		None		RPLC	MS	–	–	^[39]

9-CMA: 9-chloromethyl anthracene, DBD-PZ: 7-(N,N-dimethylaminosulfonyl)-4-piperazino-2,1,3-benzoxadiazole.

4. Analytical methods for amino acid metabolites in biological samples

Target Compounds	Biological Sample	Sample Treatment	Derivatization Reagent		Separation Mode		Detection Method		LOD	Recovery	Ref.
Kinurenic acid	Rat plasma	Centrifugation		None	RPLC	FL: 251/398 nm			0.16 nM	97–98%	^[40]
3 Trp metabolites	Mouse plasma and brain	Centrifugation		None	RPLC			UV, FL	0.03–1.33 µM	83–116%	^[41]
6 Trp metabolites	Pig urine, plasma	Centrifugation		None	RPLC			MS	10–100 ng/mL (LOQ)	–	^[42]
Glycated Trp	Chicken plasma	Solvent extraction		None	RPLC			MS	–	–	^[43]
PHP-THβC	Chicken plasma	Cation-exchange resin		None	RPLC			MS	–	–	^[44]
5 Trp and Tyr metabolites	Human urine	Centrifugation		None	RPLC			UV: 220, 280 nm, FL: 280/350, 315/425 nm	–	–	^[45]
DOPAC, HVA	Rat kidney	Microdialysis		Ethylenediamine	Ion exchange chrom atography			FL: 417/495 nm	50, 100 fmol	–	^[46]
Nicotinic acid	Human plasma	Solvent extraction		None	RPLC			MS/MS	6.57 ng/mL (LOQ)	70–72%	^[47]
Glutaric acid, 3-HG	Human urine	Centrifugation		DAABD-AE	RPLC			MS/MS	20–25 nM	94–121%	^[48]
64 amino acid derivatives	Human urine, pancreatic cancer cells	Centrifugation		DmPABr	RPLC			MS/MS	0.11–2192 nM	–	^[49]

PHP-THβC: (1R, 3S)-1-(D-gluco-1, 2, 3, 4, 5-pentahydroxypentyl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid, DOPAC: 3,4-dihydroxyphenylacetic acid, HVA: homovanillic acid, 3-HG: 3-hydroxyglutaric acid, DAABD-AE: 4-[2-(N,N-dimethylamino)ethylaminosulfonyl]-7-(2-aminoethylamino)-2,1,3-benzoxadiazole, DmPABr: dimethylaminophenacyl bromide

5. Analytical methods for perfluorinated carboxylic acids (PFCAs) in biological samples

Target Compounds

Biological Sample

Sample Treatment

Derivatization Reagent

Separation Mode

Detection Method

LOD

Recovery

Ref.

3 PFASs

Human tissues and blood

Solid phase extraction

None

RPLC

3 µg/L

80–101%

^[50]

10 PFASs

Two bivalves shells, soft tissues

Solid phase extraction

None

RPLC

MS/MS

0.05–0.43 ng/g

92–104%

^[51]

18 PFASs

Human urine and serum

Solid phase extraction

None

RPLC

MS/MS

0.1 µg/L

94–104%

^[52]

21 PFASs

Human serum

Solid phase extraction

None

RPLC

MS/MS

0.008–0.19 µg/L

85–114%

^[53]

6 PFASs

Human plasma

µ-SPE

None

RPLC

MS/MS

21–65 ng/L

88–102%

^[54]

6 PFASs

Human serum

Deproteinization

MASH

RPLC

MS/MS

0.07–0.42 µg/L

96–100%

^[55]

11 PFASs

Human blood

Solvent extraction

None

RPLC

MS/MS

0.06–0.14 µg/L

67–112%

^[56]

20 PFASs

Human plasma, BCS

Centrifugation

None

RPLC

MS/MS

0.024–0.096 µg/L (LOQ)

83–103%

^[57]

PFASs: polyfluoroalkyl substances, MASH: 10-methyl-acridone-2-sulfonohydrazide.

6. Analytical methods for α-keto acids and 2-hydroxyglutaric acid (2-HG) in biological samples

Target Compounds

Biological Sample

Sample Treatment

Derivatization Reagent

Separation Mode

Detection Method

LOD

Recovery

Ref.

4 α-Keto acids

Human serum

Centrifugation

OPD

RPLC

FL: 350/410 nm

1 µM

86–109%

^[58]

7 α-Keto acids

Human neutrophil

Centrifugation

OPD

RPLC

FL: 360/415 nm

0.035–0.125 µM

79–108%

^[59]

3 α-Keto acids

Human CML cell

Gel extraction

OPD

RPLC

FL: 360/415 nm

18–40 nM

84–96%

^[60]

6 α-Keto acids

Human CML cell

Centrifugation

DMB

RPLC

FL: 367/446 nm

1.3–5.4 nM

86–118%

^[61]

3 α-Keto acids

Mouse tissue

Acid extraction

OPD

RPLC

5 nM

76–95%

^[62]

10 α-Keto acids

Rat plasma

Centrifugation

O-PFBO

RPLC

MS/MS

0.01–0.25 µM

96–109%

^[63]

3 α-Keto acids

Human plasma

Centrifugation

None

RPLC

MS/MS

0.04 µg/mL

81–98%

^[64]

(R)-2-HG

Human serum

Solid phase extraction

DATAN

RPLC

MS/MS

0.060 µM

31–32%

^[65]

(R)-2-HG

Human urine, cancer tissues

Solvent extraction

TSPC

RPLC

MS/MS

1.2 fmol

88–109%

^[66]

OPD: o-phenylenediamine, DMB: 1,2-diamino-4,5-methylenedioxybenzene, O-PFBO: O-(2,3,4,5,6-pentafluorobenzyl)oxime, DATAN: (+)-o,o’-diacetyl-l-tartaric anhydride, TSPC: N-(p-toluenesulfonyl)-L-phenylalanyl chloride.

7. Analytical methods for 2-aminothiazoline-4-carboxylic acid (ATCA), 2-methylthiazolidine-4-carboxylic acid (MTCA), and 2-thiothiazolidine-4-carboxylic acid (TTCA) in biological samples

Target Compounds

Biological Sample

Sample Treatment

Derivatization Reagent

Separation Mode

Detection Method

LOD

Recovery

Ref.

ATCA

Rat plasma and organ

Solid phase extraction

None

RPLC

MS/MS

–

^[67]

ATCA

Human urine

MISBSE

None

RPLC

MS/MS

5 µg/L

–

^[68]

ATCA

Rat plasma

Solid phase extraction

None

RPLC

MS/MS

12 µg/L

–

^[69]

ATCA

Human postmortem blood

Solid phase extraction

None

HILIC

MS/MS

2.5 µg/L

81–89%

^[70]

ATCA

Human postmortem blood

Solid phase extraction

None

HILIC

MS/MS

9 µg/L (LOQ)

88–96%

^[71]

ATCA

Human post-mortem blood

Liquid-liquid extraction

None

HILIC

MS/MS

0.43 µg/L

86–101%

^[72]

MTCA

Human blood and urine

Centrifugation

Acetic anhydride

RPLC

MS/MS

0.1 mg/L

–

^[73]

TTCA

Urine

Acid extraction

None

RPLC

UV: 271 nm

35 µg/L

78–87%

^[74]

MISBSE: molecularly imprinted stir bar sorption extraction.

8. Analytical methods for other carboxylic acids in biological samples

Target Compounds

Biological Sample

Sample Treatment

Derivatization Reagent

Separation Mode

Detection Method

LOD

Recovery

Ref.

7 Bile acids

Human saliva

SPE and solvent extraction

2-Picolylamine

RPLC

MS/MS

1.5–5.6 fmol

–

^[75]

3 Bile acids, 8 fatty acids

Human plasma and saliva

Solid phase extraction

APBQ

RPLC

MS/MS

0.19–0.51 fmol

–

^[76]

7 Bile acids, 9 fatty acids

Human serum

Solvent extraction

DBCETS

RPLC

FL: 300/395 nm

0.28–0.70 ng/mL

92–102%

^[77]

4 Bile acids

C. bovis

Centrifugation

2-bromo-4′-nitroacetophenone

RPLC

UV: 263 nm

0.25–0.31 ng

94–99%

^[78]

7 Bile acids

Human feces

Solid phase extraction

Phenacyl bromide

RPLC

UV: 254 nm

1.22–1.46 pmol

72–102%

^[79]

Human feces

Solid phase extraction

None

PRLC

MS/MS

–

^[79]

Dihydroxyoxocholestenoic acids

Human CSF and plasma

Solid phase extraction

Isotope-label ed Girard’s P Reagent

RPLC

0.02–0.05 ng/mL

–

^[80]

7 THGC glucuronides

Human urine

Centrifugation

Isotope-labeled DAPPZ

RPLC

MS/MS

0.008–0.16 µg/mL (LOQ)

–

^[81]

Orotic acid

Urine

Dilution

None

RPLC

MS/MS

0.15 µM

–

^[82]

Metabolome

Human urine

Centrifugation

Isotope-label ed DmPABr

RPLC

–

^[83]

Metabolome

Human urine

Centrifugation

Isotope-labeled dansyl hydrazine

RPLC

–

^[84]

APBQ: 1-(3-aminopropyl)-3-bromoquinolinium bromide, DBCETS: 2-(7H-dibenzo[a,g]carbazol-7-yl)ethyl 4-methylbenzenesulfonate, DAPPZ: 1-[(4-dimethylaminophenyl)-carbonyl]piperazine, DmPABr: dimethylaminophenacyl bromide.

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Makoto Tsunoda

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Table of Contents

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1. Introduction

2. Analytical methods for fatty acids in biological samples

3. Analytical methods for TCA cycle and glycolysis-related compounds in biological samples

4. Analytical methods for amino acid metabolites in biological samples

5. Analytical methods for perfluorinated carboxylic acids (PFCAs) in biological samples

6. Analytical methods for α-keto acids and 2-hydroxyglutaric acid (2-HG) in biological samples

7. Analytical methods for 2-aminothiazoline-4-carboxylic acid (ATCA), 2-methylthiazolidine-4-carboxylic acid (MTCA), and 2-thiothiazolidine-4-carboxylic acid (TTCA) in biological samples

8. Analytical methods for other carboxylic acids in biological samples

References