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Table 2 List of studies reporting candidate biomarkers for herb and spice intake

From: Herbs and Spices- Biomarkers of Intake Based on Human Intervention Studies – A Systematic Review

Dietary factor Study design Subjects Analytical method Sample type Discriminating metabolites/candidate biomarkers Primary Ref.
Anise (anethole admn.) Acute human study. [methoxy-14C]-labeled compound 5 (males) Radiochemical (14C labeled) and HPLC Urine (2 h–10 h, 24 h, and 48 h) 4-methoxybenzoic acid, 4-methoxyhippuric acid, 3 unknown compounds [36]
Anise-based alcoholic drink Dose escalating study (120 ml, 200 ml, 360 ml “Helenas Ouzo” (anethole-containing drink) 1 HS-SPME-GC–MS Serum (1, 2, 4, 8, and 24 h) Anethole [37]
Observational study: drivers under the influence of alcoholic-containing anethole drink 50 Serum
Capsicum sp. Chili pepper (capsule) Acute crossover study (5 g of capsicum extract) 12 (males) HPLC Plasma Capsaicin [41]
Capsicum sp. CH-19 sweet non-pungent red pepper (capsule) Double-blind, randomized, placebo-controlled, dose-escalating (15 or 30 mg capsinoids extract) 24 (males) LC-MS/MS and HPLC-UV Plasma (15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h) Capsiate, dihydrocapsiate, nordihydrocapsiate, vanillyl alcohol [150]
Capsicum sp. Paprika carotenoids Case study. 200 ml paprika carotenoid beverage 5 (young, healthy) HPLC-UV-VIS and Q-TOF-MS/MS Plasma (0 week, 2 weeks, 4 weeks), erythrocytes β-cryptoxanthin, cucurbitaxanthin A, cryptocapsin, lutein, zeaxanthin, capsanthin, capsanthone [42]
Cinnamon Four-way crossover study 24 HPLC MS/MS Plasma and urine 7-hydroxycoumarin [48]
Fennel (fennel tea) Single-dose acute study (500 ml of fennel tea) 7 LC-MS/MS and GC-GC-MS Urine (1.5, 4, 8, 14, 24 h) Estragole, 1′-hydroxyestragole, trans-Anethole, -Allylphenol-G [63]
Dose-escalation study (250, 500, 1000 ml fennel tea). 1 Plasma (0.75,1.5, 2, 2.5 h)
Fennel, basil, and tarragon 15 mL fennel extract; 15 ml tarragon extract; 15 ml basil brewed NP IS-R-DLLME and HPLC Plasma (2 h, 4 h, and 8 h) and Urine (3 h, 6 h, and 9 h) Para-anisaldehyde trans-anethole estragole [38]
Ginger (extract) Acute single dose: 2 g ginger extracts 9 (healthy) LC-MS/MS Plasma (0.25 h, 0.5 h, 0.75 h, 1 h, 2 h, 4 h, 6 h, 10 h, 24 h, 48 h, and 72 h) 10-Gingerol, 6-Shogaol, 6-Gingerol-G, 8-Gingerol-G 10-Gingerol-G, 6-Shogaol-G 6-Gingerol-S, 8-Gingerol-S, 10-Gingerol-S, 6-Shogaol-S [70]
Multiple dose: 24-day randomized controlled trial. 250 mg ginger extract 30 (healthy) Plasma (0–24 h) and colon (biopsy) 6-Gingerol-G (plasma), 10-Gingerol-G (plasma), 6-Gingerol-S (plasma), 10-Gingerol-G (colon), 10-Gingerol-S (colon)
Multiple dose: 24-day randomized controlled trial. 250 mg ginger extract 20 (high-risk colorectal cancer) Plasma (0-24 h) and colon (biopsy) 6-Gingerol-G (plasma), 10-Gingerol-G (plasma), 6-Gingerol-S (plasma) 10-Gingerol-G (colon), 10-Gingerol-S (colon)
Ginger Dose escalation study: 100 mg, 250 mg, 500 mg, 1 g, 1.5 g, 2 g ginger extract (capsule) 27 (healthy) HPLC-ECD, HPLC-UV Plasma (15 min, 30 min, and 45 min, 1 h, 2 h, 4 h, 6 h, 10 h, 24 h, 48 h, and 72 h) 6-Gingerol-G, 8-Gingerol-G, 10-Gingerol-G, 6-Shogaol-G, 6-Gingerol-S, 10-Gingerol-S [69]
Ginger (ginger tea) Acute study. 2× (18 g/bag) ginger tea (focused on the metabolism of shogaol) 3 (healthy males) LC/ESI-MS/MS Urine (0–2 h, 2–4 h, 4–6 h, 6–9 h, 9–12 h, and 12–24 h) 5-Cys-6S, 5-NAC-6S, 5-Cys-Gly-6S, 5-Cys-M6, 5-NAC-M6, 5-Cys-Gly-M6, 5-Cys-8S, 5-Cys-M6’, 5-Cys-10S, 5-Cys-M6" [71]
Marjoram (extract) Acute single oral dose (3.75 g) of O. onites extract 6 (healthy) HPLC-CEAD Urine (24 h, 48 h) Protocatechuic acid, p-hydroxybenzoic acid, caffeic acid, ferulic acid, syringic acid, vanillic acid, p-coumaric acid, 3,4-dihydroxyphenylacetic acid, m-hydroxyphenylacetic acid [97]
Nutmeg Acute oral dose in rats (100 mg/kg body mass) of EL, MY, and SA or a single 500 mg/kg body mass of nutmegs 2 rats × each substance and dose GC-MS Urine (24 h) O-demethyl elemicin*, O-demethyl dihydroxy elemicin*, demethylenyl myristicin*, dihydroxy myristicin*, demethylenyl safrole* [73]
Observational exploratory toxicological study: after nutmeg abuse (~ 5 nutmegs) 1
Oregano (extract) Oregano extract (25, 75, or 225 mg/kg 15 mice HPLC–MS/MS Plasma and brain tissue Carvacrol [95]
Parsley Randomized crossover with two 1-week intervention periods in succession, supplemented with parsley 20 g parsley/MJ 14 (healthy) HPLC-DAD Urine (24 h) Apigenin [108, 109]
Parsley Acute human study. (149.45 ± 35.21 g parsley) 11 (healthy) HPLC-ECD Plasma (4–11 h, 28 h), urine (24 h), and red blood cells Apigenin [102]
Peppermint oil (capsule) Acute pharmacokinetic study. Intake of 0.4 ml peppermint oil in either colpermin or gelatine capsules (91–97 mg capsule) 6 (healthy) NP Urine (24 h) Menthol-G [117]
6 (ileostomy)
Peppermint oil Acute randomized intake of 0.6 ml peppermint oil in either Colpermin or Mintec preparations 13 (healthy) GC-MS Urine (2 h-interval for 14 h + single overnight (10 h) Menthol-G [116]
Peppermint oil (capsule) 180 mg peppermint oil enteric-coated capsule (peroral administration) 4 (males) GC-FID Urine (2-h interval up to 14 h) Menthol-G [118]
Peppermint oil (capsule) Acute (400 mg peppermint oil in enteric-coated capsule) and repeated 4 weeks later 5 (healthy) 2H-NMR Urine (2 h, 4 h, 6 h, and 8 h) Menthol-G [120]
Peppermint oil (capsule) (1) 400 mg of enteric-coated peppermint oil capsules and 6 g of 99% [U-13C] glucose 1 (female) 13C-NMR Urine (2-4 h) 13C-menthol-G [119]
(2) Primed infusion of [U-13C] glucose + 400 mg enteric-coated peppermint oil capsules 4 (severe heart failure) Urine (2 h)
Peppermint oil (L-menthol preparation) Escalating-single-dose, randomized, double-blind, placebo-controlled (menthol preparation, 80–320 mg). Intragastric spraying of peppermint oil 24 (males) GC-MS Plasma (5, 10, 30, 60, 120, and 240 min and 8, 12, and 24 h after each dose) Menthol, menthol-G, M7, M9, M11, M29 [121]
Urine (before dosing (−12–0 h) and 0–4 h, 4–8 h, 8–12 h, and 12–24 h after Menthol-G, M2, M3–11, M12, M13–18, M19–21, M22–28, M29, M30–32.
Rosemary (extract) Acute, controlled, randomized study. Rosemary extract enriched in carnosic acid 40% (w/w) 24 Zucker rats HPLC/QTOF-MS and HPLC-UV Gut, liver, plasma, brain, Carnosic acid-G, carnosol-G, rosmanol-G, carnosic acid 12 methyl ether, 5,6,7,10-tetrahydro-7-hydroxyrosmariquinone, carnosic glutathione oxidized, carnosol-S, rosmanol-S, rosmarinic acid, carnosic cysteine, carnosic glutathione, rosmadial-G, rosmanol, ipirosmanol, epiisorosmanol, rosmadial/rosmanol quinone, rosmanol/epirosmanol methyl ether, carnosol, rosmadial methyl ether, epirosmanol ethyl ether, epiisorosmanol methyl ether, carnosol methyl ether, carnosic acid. [100]
Subchronic, controlled, randomized study Rosemary extract enriched in carnosic acid 40% (w/w) (64 days)
Saffron (tea) Single-dose acute study. 200 mg saffron in 150 ml water (saffron tea) 4 (healthy) SPE-HPLC-DAD Plasma (0 h, 2 h, and 24 h) cis-Crocetin, trans-Crocetin [126]
Saffron (purified crocetin) Open-label, single dose escalation of crocetin (7.5, 15 and 22.5 mg) 10 (healthy) HPLC Plasma (1 , 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h) Crocetin [127]
Sage (tea) Acute human study (1.02 mg 1,8-cineole) in sage tea 1 (female) SPME-GC-MS and LC-MS/MS Plasma (0.75 h, 1.7 h, 3.25 h, 6.75 h, and 24 h) and urine (2 h, 5 h, 7 h, 10 h, 17 h, 21 h, 28 h, 32 h, 35 h, 44 h, 50 h, 53 h, 60 h, and 69 h) 1,8-cineole, 2-hydroxy-1,8-cineole, 3-hydroxy-1,8-cineole, 7-hydroxy-1,8-cineole, 9-hydroxy-1,8-cineole. [130]
Thyme (tablet) Acute study. A single dose of a Bronchipret® TP (tablet equivalent to 1.08 mg thymol) 12 HS-SPME-GC-MS and LC-MS/MS Plasma (0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 14 h, 24 h, 31 h, 38 h, 48 h, 55 h, 62 h, and 72 h) Thymol-S [151]
Urine (0 to 3 h, 3 to 6 h, 6 to 9 h, 9 to 14 h, 14 to 24 h, 24 to 31 h, 38 to 48 h, 48 to 55 , 55 to 62 h, and 62 to 72 h) Thymol-G, thymol-S
Thyme Acute intake of 1.5 g of thyme extract 12 Wistar rats μSPE-UPLC-MS/MS Plasma Thymol-S, thymol-G, luteolin-S, luteolin-G, hydroxyphenylpropionic acid-S, coumaric acid-S, caffeic acid-S, ferulic acid-S, ferulic acid-G, hydroxybenzoic acid, and dihydrophenylpropionic acid-S [98]
Thyme (olive oil enriched with thyme polyphenols) Randomized, double-blind, controlled, cross-over trial. Administration of 25 ml/day (VOO)/VOO + PC/VOO + PC + PC of thyme 33 (hypercholesterolemic) μSPE-UPLC-ESI-MS/MS Plasma Thymol-S, hydroxyphenylpropionic acid-S, caffeic acid-S [99]
Urine (24 h) Thymol-S, Thymol-G, hydroxyphenylpropionic acid-S, p-cymene-diol-G, caffeic acid-S
Thyme (olive oil enriched with thyme) (1) In vitro colonic fermentation (0 to 48 h) 3 (healthy) UPLC-ESI-MS/MS and GC-FID Feces (in vitro fermentation) Thymol, carvacrol, 2-(3′,4′-dihydroxyphenyl) acetic acid, 2-(4′-hydroxyphenyl) acetic acid, phenylacetic acid, 3-(4′-hydroxyphenyl) propionic acid, phenylpropionic acid. [96]
2-(3′,4′-dihydroxyphenyl) acetic acid, 2-(4′-hydroxyphenyl) acetic acid, Phenylacetic acid, 3-(4′-hydroxyphenyl) propionic acid, phenylpropionic acid
Caffeic acid, p-coumaric acid, 3-(3′, 4′-dihydroxyphenyl) propionic acid; hydroxyphenylpropionic acid; phenylpropionic acid, 2-(3′,4′-dihydroxyphenyl) acetic acid; 2-(4′-hydroxyphenyl) acetic acid; phenylacetic acid
3-(3′, 4′-dihydroxyphenyl) propionic acid; hydroxyphenylpropionic acid; phenylpropionic acid, 2-(3′,4′-dihydroxyphenyl) acetic acid, 2-(4′-hydroxyphenyl) acetic acid; phenylacetic acid
(2) Human intervention study: 25 ml/day of a thyme phenol-enriched olive oil for 3 weeks 10 Feces (in vivo, (0-3wk) Carvacrol, 2-(4-hydroxyphenyl) acetic acid, 3-(3′-4′-dihydroxyphenyl) propionic acid, hydroxyphenylpropionic acid, phenylpropionic acid
Turmeric (curcuminoids in capsule) Randomized double blind placebo (1 g/day, 4 g/day, placebo), 6 months 31 (elderly) LC-MS/MS Plasma (2–2.5 h after 1 month) Curcumin, DMC BDMC, THC, ferulic acid, vanillic acid [132]
Turmeric (curcuminoids in capsule) Acute study 2 (healthy) LC-MS/MS Plasma COG [141]
Turmeric (curcuminoidsin nanoemulsion) Acute study (2 g nanoemulsion curcuminoids) 2 (healthy) LC-MS/MS Plasma Curcumin, COG, COS, DMC, BDMC, and THC [142]
Turmeric (curcuminoids in capsule) Nonrandomized, open-label, phase II trial (starting dose 8 g curcuminoids) 8 weeks 25 (pancreatic cancer) LC-MS Plasma (1 h, 2 h, 6 h, 24 h, 48 h, 72 h, day 8 and after 4 weeks COG and COS [140]
Turmeric (curcuminoids in capsule) Dose escalation. 450–3600 mg/day 1 week 12 (hepatic metastasis from colorectal cancer) HPLC-UV, LC-MS Plasma and liver tissue Hexahydrocurcumin (liver), hexahydrocurcuminol (liver), curcumin (plasma), COG (plasma), COS (plasma). [143]
Turmeric (curcuminoids in capsule) Acute study. 12 (colorectal carcinoma) HPLC-UV HPLC-MS Plasma and colorectal tissue Curcumin (plasma and colorectal tissue), COG and COS (colorectal tissue) [6]
Turmeric (curcuminoids-different administration types) Randomized double blind crossover study with formulated (CP, CTR, CHC) and unformulated (CS) curcumin 12 (healthy) LC-MS/MS Plasma (1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, and 12 h) Curcumin, DMC, BDMC, THC [138]
Turmeric (curcuminoids in capsule) 14-day intervention (2.35 g capsule) 24 (colorectal cancer) UPLC-UV, LC-MS/MS Plasma, urine and colon tissue Curcumin, BDMC, DMC, BDMC-S, DMC-S, COS, COG, BDMC-G, DMC-G [147]
Turmeric (Theracurmin®) Acute dose escalation 150 mg and 210 mg 6 (healthy) LC-MS/MS Plasma (0 h, 1 h, 2 , 4 h, 6 , 24 h) Curcumin [152]
Turmeric (Theracurmin®) Multi-week dose escalation 16 (pancreatic or biliary tract cancer) LC-MS/MS Plasma (2 h) Curcumin [153]
Turmeric (turmeric fresh derived curcuminoids vs. std. curcumin) Multi-week double crossover study. 250 mg/kg body weight 18 (mice) LC-DAD-ESI-MS/MS Plasma (0 h, 0.5 , 1 h, 3 h, 5 h, 8 h, 12 h) Curcumin, DMC, BMDC [149]
Acute, single-blind crossover study, 100 mg, 250 mg, 1000 mg 15 (healthy)
Turmeric (C3 complex) Acute study. 1 single dose (4 g) 8 (healthy) HPLC Serum Curcumin [154]
3–4-week intervention study. (8 g/day) 15 (with HNSCC)
Turmeric (curcuma extract capsule) Dose escalation: 440 mg–2200 mg/day. 4 months 15 (colorectal cancer) HPLC-UV Blood, urine, feces COS (only detected in feces) [25]
Turmeric (C3 complex) Dose escalation study. 4-month intervention (450, 900, 1800, 3600 mg). 4 months 15 (colorectal adenocarcinoma patients) LC-MS Plasma, urine, feces Curcumin (plasma, urine, feces), COG (plasma, urine), DMC (plasma, urine), BDMC (plasma), DMC-G (plasma, urine), DMC-S (plasma) COS (plasma, urine, and feces). [145]
Turmeric (C3 complex, 10 or 12 g) Acute study 12 (healthy) HPLC Plasma COG and COS [139]
Turmeric 3-month intervention with different doses each group (500, 1000, 2000, 4000, 8000 mg/day) 25 cancer HPLC-UV Serum (0 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 14 h, and 24 h) Curcumin (only in serum) [144]
Urine (0–2 h, 2–4 h, 4–8 h, and 8–24 h)
Turmeric (Theracurmin®) Acute study. Curcumin in powder and Theracurmin® in liquid (30 mg). 12 Sprague-Dawley rats and 14 humans LC-MS/MS Plasma Theracurmin and curcumin [148]
Turmeric (curcumin) Dose escalation study. C3 complex adm. 500 mg, 1000 mg, 2000 mg, 4000 mg, 6000 mg, 8000 mg, 10,000 mg, and 12,000 mg) 24 HPLC Plasma and serum Curcumin (just in serum at 10000 and 12,000 mg) [146]
  1. Adm, administration; BDMC, bisdemethoxycurcumin, CEAD, coulometric electrode array detector; CHC, combination of hydrophilic carrier, cellulosic derivatives, and natural antioxidants; 13C-NMR, carbon nuclear magnetic resonance; COG, curcumin-O-glucoronide. COS, curcumin-O-sulfate; CP, curcumin phytosome formulation; CS, standardized curcumin mixture; CTR formulation with volatile oils of turmeric rhizome, Cys, cysteinyl; DAD, diode array detector; DMC, demethoxycurcumin, ECD, electrochemical detection. EL, elemicin; ESI, electrospray ionization; FID, flame ionization detector; −G, glucuronide; Gly, glycinyl; H-NMR, proton nuclear magnetic resonance; HPLC, high-performance liquid chromatography; HNSCC head and neck squamous cell carcinomas; HS-SPME, headspace solid-phase microextraction; IS-R-DLLME, in-syringe reversed dispersive liquid-liquid microextraction; LC, liquid chromatography; months, months; MJ, megajoules; MY, myristicin, M6, 1-(4′-hydroxy-3′-methoxyphenyl)-4-decen-3-ol; M6′, 1-(4′-hydroxy-3′-methoxyphenyl)-4-dodecen-3-ol; M6′′, 1-(4′-hydroxy-3′-methoxyphenyl)-4-tetradecen-3-ol; M29, menthol sulfoconjugate; M7, 9, 11, hydroxyl menthol glucuronide. M3–11, hydroxyl menthol glucuronide; M19–21, dihydroxyl menthol glucuronide. M2, aldehyde-menthol glucuronide; M13–18, carboxylate-menthol or aldehyde-hydroxyl menthol glucuronide; M29–32, sulfate conjugates; M12, dialdehydementhol glucuronide (M12); MS mass spectrometry; NAC, N-acetylcysteinyl; NP, not provided; PC, phenolic compounds; Q-TOF, quadrupole time-of-flight; S, sulfate; SA, safrole; THC, tetrahydrocurcumin; UPLC, ultra-high performance liquid chromatography; UV ultraviolet; VIS, visible; VOO, virgin olive oil. weeks, week; w/w, weight per weight; μSPE, microelution solid-phase extraction; 6S, 6-shogaol; 8S, 8-shogaol; 10S, 10-shogaol
  2. *In the study performed in rats, there were other metabolites also identified but not found in the human sample analyzed so they were not considered in this table