TABLE 14

Ontogeny profile of hepatic phase II enzymes in humans based on metabolic activity, protein expression, and mRNA expression levels

Percentages represent expression/activity relative to adult levels.

Onset of Activity and/or ExpressionAdult Levels ReachedAge-Related Changes in Activity and/or ExpressionCommentsReferences
COMT
 Catalytic activityBirth (T3: <2%)NR (12 yr: 25%)Increased slowly then decreased in elderly12–18 yr: NR. Substrate: methyepinephrine. Matrix: liver cytosol. Methods: HLC, spectrophotometryAgathopoulos et al. (1971)
GSTA1
 Protein expressionFetal development (T1–T3: 70%)Neonates–1 yrIncreased rapidly1–18 yr: ND. Methods: electrophoresis and radioimmunoassayStrange et al. (1989); McCarver and Hines (2002)
GSTA2
 Protein expressionFetal development (T1–T3: 25%)>1 yr (60%)Increased progressively1–18 yr: ND. Methods: electrophoresis and radioimmunoassayStrange et al. (1989); McCarver and Hines (2002)
GSTM
 Protein expressionFetal development (T1–T3: 20%)Neonates–1yrIncreased rapidly1–18 yr: ND. Methods: electrophoresis and radioimmunoassayStrange et al. (1989); McCarver and Hines (2002)
GSTP1
 Protein expressionFetal development (T1–T3: >1000%)Fetal developmentInconsistent pattern1–18 yr: ND. Methods: electrophoresis and radioimmunoassayStrange et al. (1989); McCarver and Hines (2002)
GSTZ1
 Catalytic activityFetal development (T1–T3: <30%)>7 yrIncreased slowly (7 yr: 75%)7–18 yr: NR. Substrate: dichloroacetic acid. Matrix: liver cytosol. Methods: HPLC coupled with radioactivity flow detectorLi et al. (2012)
 Protein expressionBirth (2.5 wk: <10%)>7 yrIncreased slowly (7 yr: 75%)7–18 yr: NR. Methods: Western blottingLi et al. (2012)
NAT
 Catalytic activityBirth (T1–T3: <3%)1.5 yrIncreased progressively11–18 yr: NR. Substrates: glycine, benzoic acid. Matrix: liver homogenates. Methods: radioactivity, spectrophotometryPacifici et al. (1991a); Mawal et al. (1997)
SULT1A1
 Catalytic activityFetal development (T1–T3: >80%)Fetal developmentPeaked at 6 mo (3-fold)6 mo to 18 yr: NR. Substrates: 1-naphtol, 2-naphtol, 4-nitrophenol, N-hydroxy-4-aminobiphenil, N-hydroxy-4-acetylaminobiphenyl. Matrix: liver cytosol. Methods: radioactivity HPLC, chromatographyPacifici et al. (1988); Cappiello et al. (1991); Gilissen et al. (1994); Richard et al. (2001)
 Protein expressionFetal development (T1–T3: 93%)Fetal developmentNo changesMethods: electrophoresis and radioimmunoassayMcCarver and Hines (2002); Duanmu et al. (2006)
SULT1A3
 Catalytic activityFetal development (T1–T3: >200%)Fetal developmentDecreased in neonates (2.5-fold)Neonates–18 yr: NR. Substrate: dopamine. Matrix: liver cytosol. Methods: radioactivity, chromatographyPowis et al. (1988); Cappiello et al. (1991); Pacifici et al. (1993); Richard et al. (2001)
SULT1E1
 Catalytic activityBirth (T1–T3: <2%)19 wk: 35%Increased progressively19–18 yr: NR. Substrate: dehydroepiandrosterone. Matrix: liver cytosolBarker et al. (1994)
 Protein expressionFetal development (T1–T3: >100% or 20%)Fetal development or 19 wk (92%)Decreased in infants (2-fold) or increased rapidly (3 wk: 69%)19–18 yr: NR. Methods: immunoblotting, Western blottingBarker et al. (1994); Duanmu et al. (2006)
SULT2A1
 Protein expressionFetal development (T1–T3: <10%)Neonates–1 yr (160%)Increased rapidlyMethods: electrophoresis and radioimmunoassayMcCarver and Hines (2002); Duanmu et al. (2006)
 mRNA expressionFetal development (T1: 30%)NRNRT2–30 yr: NR. Methods: qRT-PCREkström and Rane (2015)
TMPT
 Catalytic activityFetal development (T2: 30%)NRNRBirth–18 yr: NR. Substrate: 6-mercaptopurine. Matrix: liver cytosol. Methods: radioactivityPacifici et al. (1991b)
UGT1A1
 Catalytic activityBirth (T1–T3: <10%)Neonates or 1–2 yr (90%)Increased rapidly or progressivelyConflicting results. Substrates: bilirubin, 2-aminophenol, β-estradiol*. Matrix: liver microsomes, liver homogenates. Methods: high-pressure LC, spectrophotometry, HPLC (-MS\MS)Onishi et al. (1979); Kawade and Onishi (1981); Leakey et al. (1987); Coughtrie et al. (1988); Burchell et al. (1989); Miyagi and Collier (2011); Nie et al. (2017); Bhatt et al. (2019)
 Protein expressionFetal development (T1–T3: 10%)1–2 yr (90%)Increased progressivelyMethods: Western blotting, proteomics-HPLCMiyagi and Collier (2011); Nie et al., (2017); Bhatt et al. (2019)
 mRNA expressionBirth (T1–T3: 0.5%)6 moIncreased progressivelyBirth–6 mo: NR. 2–18 yr: NR. Methods: qRT-PCRStrassburg et al. (2002); Nie et al. (2017)
UGT1A3
 Catalytic activityFetal development (T2: 30%)NRNRT1: UD. Substrate: NA. Matrix: NAde Wildt et al., (1999); McCarver and Hines (2002)
UGT1A4
 Catalytic activityBirth (neonates: 50% or 10%)NR (12–18 yr: 44%) or 2–6 yr (80%)Increased slowly or progressivelyFetal development: NR. Substrate: trifluoperazine. Conflicting results. Matrix: liver microsomes. Methods: fluorometry, HPLC-MS/MS.Miyagi and Collier (2007); Bhatt et al. (2019)
 Protein expressionBirth (neonates: <2%)6–12 yr (70%)Increased slowlyFetal development: NR. Methods: proteomics-HLPCBhatt et al. (2019)
UGT1A6
 Catalytic activityBirth (neonates: 10% or 100%)NR (12–18 yr: 50%) or neonatesIncreased progressively or no changesFetal development: NR. Substrates: serotonin, 4-hydroxyindole. Conflicting results. Matrix: liver microsomes. Methods: ELISA assay, HPLC (-MS/MS)Miyagi and Collier (2007); Neumann et al. (2016); Bhatt et al. (2019)
 Protein expressionBirth (neonates: <5%)NR (12–18 yr: 41%) or 2–6 yrIncreased slowly or progressivelyFetal development: NR. Conflicting results. Methods: Western blotting, proteomics-HLPCMiyagi and Collier (2007); Bhatt et al. (2019)
UGT1A9
 Catalytic activityBirth (neonates: <20%)1 mo to 1 yr or 1 to 2 yr (80%)No changes or increased progressivelyFetal development: NR. Substrates: 4-methylumbelliferone**, propofol. Conflicting results. Matrix: liver microsomes. Methods: fluorometry, HPLC-MS/MSMiyagi and Collier (2007); Bhatt et al. (2019)
 Protein expressionBirth (neonates: <20%)NR (12–18 yr: 37%) or 1 mo to 1 yr: 85%Increased progressively or decreased at 2 yr (50%)Fetal development: NR. Conflicting results. Methods: proteomics-HPLC, Western blottingMiyagi and Collier (2007); Bhatt et al. (2019)
 mRNA expressionBirth (T2: UD)>2 yr (2 yr: 68%)Increased slowlyFetal development–6 mo: NR. 2–18 yr: NR. Methods: qRT-PCRStrassburg et al. (2002)
UGT2B4
 mRNA expressionBirth (T2: UD)>2 yr (2 yr: <40%)NRFetal development–6 mo: NR. 2–18 yr: NR. Methods: qRT-PCRStrassburg et al. (2002)
UGT2B7
 Catalytic activityFetal development (T1–T3: 13%)NR (12–18 yr: 40%–50%)Increased slowlyConflicting results. Substrates: epirubicine, morphine, naloxone. Matrix: liver microsomes. Methods: HPLC-MS/MS, HPLC coupled with fluorescencePacifici et al. (1982, 1989); Zaya et al. (2006); Bhatt et al. (2019)
 Protein expressionBirth (neonates: <13%)NR (12–18 yr: 70%)Increased slowlyFetal development: NR. Conflicting results. Methods: electrophoresis and immunoblotting, proteomics-HPLCZaya et al. (2006); Bhatt et al. (2019)
 mRNA expressionBirth (T2: UD)6 mo to 1 yrIncreased rapidlyFetal development–6 mo: NR. Methods: qRT-PCR, qPCRStrassburg et al. (2002); Neumann et al. (2016)
UGT2B15
 Catalytic activityBirth (neonates: <10%)NR (12–18 yr: 50%)Increased slowlyFetal development: NR. Substrate: oxazepam. Matrix: liver microsomes. Methods: HPLC-MS/MSBhatt et al., (2019)
 Protein expressionFetal development (T3: <20%)12–18 yr: (80%)Increased slowlyMethods: immunoquantification, proteomics-HPLCDivakaran et al. (2014); Bhatt et al. (2019)
UGT2B17
 Catalytic activityFetal development (T1–T3: 10%)12–18 yr: (80%)Increased slowlySubstrate: testosterone. Matrix: liver microsomes. Methods: High-pressure LC, HPLC (-MS/MS)Leakey et al. (1987); Coughtrie et al. (1988); Neumann et al. (2016); Bhatt et al. (2018)
 Protein expressionBirth (neonates: <5%)NR (12–18 yr: 60%)Increased slowlyFetal development: NR. Methods: proteomics-HPLCBhatt et al. (2018)
  • HLC, high performance liquid chromatography; HPLC, high-performance LC; NA, not available; ND, not detectable; NR, not reported; qPCR, quantitative polymerase chain reaction; qRT-PCR, quantitative reverse-transcriptase polymerase chain reaction; TMPT, thiopurine-methyltransferase; T1, trimester 1 of fetal life; T2, trimester 2 of fetal life; T3, trimester 3 of fetal life; UD, undetected.

  • * β-estrsdiol-3-glucuronide formation, **4-MU coincubated with niflumic acid.