TABLE 7

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

Percentages represent expression/activity relative to adult levels.

Onset of Expression/ActivityAdult Levels ReachedAge-Related Changes (% of Adult) in Expression/Activity after BirthCommentsReferences
ADH1A
 Protein expressionBirth: 37.0%1–6 yrIncreased progressivelyAge at which 50% of maximum protein expression was reached: 10.1 mo. Adult age: 18 yr. Methods: LC-MS/MSBhatt et al. (2017)
ADH1B
 Protein expressionBirth: 12.6%1–6 yrIncreased progressivelyAge at which 50% of maximum protein expression was reached: 9.3 mo. Adult age: 18 yr. Methods: LC-MS/MSBhatt et al. (2017)
ADH1C
 Protein expressionBirth: 2.7%1–6 yrIncreased progressivelyAge at which 50% of maximum protein expression was reached: 12.3 mo. Adult age: 18 yr. Methods: LC-MS/MSBhatt et al. (2017)
ALDH1A1
 Protein expressionBirth: 36.5%1–6 yrIncreased progressivelyAge at which 50% of maximum protein expression was reached: 10.9 mo. Adult age: 18 yr. Methods: LC-MS/MSBhatt et al., (2017)
CES1
 Catalytic activityPediatric: 42.0%NRIncreasedAdult age: 18 yr. Substrate: oseltamivir Methods: depletion assay.Boberg et al. (2017)
 Protein expressionBirth: 19%–34%3 wk to 6 yr (Boberg et al., 2017); 18 yr (Hines et al., 2016)Increased rapidlyAdult age: 18 yr. Methods: LC-MS/MS (Boberg et al., 2017), Western blotting (Hines et al., 2016)Hines et al. (2016); Boberg et al. (2017)
CES2
 Protein expressionBirth: 34%–43%3 wk to 6 yrIncreased progressivelyAdult age: 18 yr. Methods: LC-MS/MS (Boberg et al., 2017), Western blotting (Hines et al., 2016)Hines et al. (2016); Boberg et al. (2017)
FMO3
 Protein expressionBirth: 46.4%6–12 yrIncreased slowlyAdult age: 18 yr. Methods: LC-MS/MSXu et al. (2017)
CYP total
 ProteinFetal development (57%–21%)NRInconsistent patternMethods: Western blot, immunoblotCazeneuve et al. (1994); Shimada et al. (1994, 1996); Tateishi et al. (1997); Treluyer et al. (1997)
 mRNAFetal development (40%)NRNRMethods: RNase protection assayShephard et al. (1992)
CYP1A2
 Catalytic activityFetal development (4%)5–15 yrIncreased slowlySubstrates: ECOD (Mäenpää et al., 1993), Imipramine, Methoxyresorufin (Sonnier and Cresteil, 1998), caffeine (Cazeneuve et al., 1994). Matrix: microsomes. Methods: spectrophotometry (Mäenpää et al., 1993), radioactivity (Sonnier and Cresteil, 1998), fluorimetry (Sonnier and Cresteil, 1998), HPLC (Cazeneuve et al., 1994)Mäenpää et al. (1993); Cazeneuve et al. (1994); Sonnier and Cresteil (1998)
 ProteinFetal development (0%–13%)1–5 yr: 50%–100%Increased slowlyMethods: immunoblot, Western blotBerthou et al. (1988); Ratanasavanh et al. (1991); Shimada et al., (1994); Tateishi et al. (1997); Sonnier and Cresteil, (1998); Song et al. (2017)
 mRNANR (ND in fetal tissue)NRNR (D in adult tissue)Methods: PCR, RNA blotRatanasavanh et al. (1991); Hakkola et al. (1994); Yang et al. (1995)
CYP2A6
 Catalytic activityFetal development (0.6%)5–15 yrIncreased progressivelySubstrate: coumarin, nicotine. Matrix: microsomes. Methods: NRShimada et al. (1996); Hakkola et al. (1998); Upreti and Wahlstrom, (2016)
 ProteinFetal development (T3: 65%)1–15 yrInconsistent patternMethods: Western blot, immunoblotShimada et al. (1994); Shimada et al. (1996); Tateishi et al. (1997); Upreti and Wahlstrom (2016)
 mRNANR (ND in fetal tissue)NRNR (D in adult tissue)Methods: PCRHakkola et al. (1994)
CYP2C
 ProteinFetal development (<1%)NR (3–12 mo: 34%)Increased rapidlyMethods: Western blot, immunoblotShimada et al. (1994, 1996); Treluyer et al. (1997)
 mRNAFetal development (6%–60%)NR (1–5 yr: 87%)Increased slowlyMethods: Northern blot, RNA blotRatanasavanh et al. (1991); Treluyer et al. (1996); Treluyer et al. (1997)
CYP2C8
 ProteinFetal development (28%)NR (>7 yr: 100%)NR (increased)Methods: Western blot, immunoblotTateishi et al. (1997); Naraharisetti et al. (2010); Song et al. (2017)
 mRNAFetal development (D)NR (>7 yr: 100%)NR (no changes > 7 yr)Methods: PCRHakkola et al. (1994); Naraharisetti et al. (2010)
CYP2C9
 ProteinFetal development (100%)No changesMethods: Western blot, immunoblotTateishi et al. (1997); Koukouritaki et al. (2004)
 mRNAFetal development (T1-2: ND and T3: 13%)28 daysIncreased progressivelyMethods: Northern blotTreluyer et al. (1997)
CYP2C18
 mRNAFetal development (40%)28 daysInconsistent patternMethods: Northern blotTreluyer et al. (1997)
CYP2D6
 Catalytic activityFetal development (1.2%–3.7%)NR (28 days: 27.5%)Increased rapidlySubstrate: dextromethorphan. Matrix: microsomes. Methods: HPLCTreluyer et al. (1991); Jacqz-Aigrain and Cresteil (1992); Stevens et al. (2008)
 ProteinFetal development (8%–82%)1–5 yrIncrease rapidlyMethods: Western blotting (Tateishi et al., 1997; Stevens et al., 2008), immunoblotting (Treluyer et al., 1991; Jacqz-Aigrain and Cresteil, 1992; Shimada et al., 1996)Treluyer et al. (1991); Jacqz-Aigrain and Cresteil (1992); Shimada et al. (1996); Tateishi et al. (1997); Stevens et al. (2008)
 mRNAFetal development (50%–90%)1 daysNon-linear patternMethods: slot blot (Treluyer et al., 1991; Jacqz-Aigrain and Cresteil, 1992), PCR (Hakkola et al., 1994)Treluyer et al. (1991); Jacqz-Aigrain and Cresteil (1992); Hakkola et al. (1994)
CYP2E1
 Catalytic activityFetal development (3%–20%)NR (5–15 yr: 81%)Increased slowlySubstrate: EtOH (Carpenter et al., 1996; Miller et al., 1996), chlorzoxazone (Vieira et al., 1996). Matrix: microsomes. Methods: immunoblotCarpenter et al. (1996); Miller et al. (1996); Vieira et al. (1996)
 ProteinFetal development (1.5%–70%)1–5 yrIncreased slowlyMethods: Western blot, immunoblotShimada et al. (1994, 1996); Miller et al. (1996); Treluyer et al. (1996); Vieira et al. (1996); Tateishi et al. (1997); Johnsrud et al. (2003)
 mRNAFetal development (2%–6%)NR (3–12 mo: 40%)Increased slowlyMethods: PCRHakkola et al. (1994); Vieira et al. (1996)
CYP4A
 ProteinFetal development (200%)NR (1–5 yr: 169%)Decreased slowlyMethods: Slot blotTreluyer et al. (1996)
CYP total
 ProteinFetal development (57%–21%)NRInconsistent patternMethods: Western blot, immunoblotCazeneuve et al. (1994); Shimada et al. (1994, 1996); Tateishi et al. (1997); Treluyer et al. (1997)
 mRNAFetal development (40%)NRNRMethods: RNase protection assayShephard et al. (1992)
CYP3A
 ProteinFetal development (65%–80%)1–5 yrIncreased slowlyMethods: Western blot, immunoblotRatanasavanh et al. (1991); Shimada et al. (1994, 1996); Lacroix et al. (1997); Tateishi et al. (1997)
CYP3A4
 Catalytic activityFetal development (6%–3%)1–5 yrIncreased slowlySubstrate: testosterone. Matrix: microsomes. Methods: radioactivity (Lacroix et al., 1997)Shimada et al. (1996); Lacroix et al. (1997); Leeder et al. (2005)
 ProteinFetal development (T1-2: 12.5% and T3: 33%)NR (5–15 yr: 33%)Increased slowlyMethods: immunoblotStevens et al. (2003); Pope et al. (2005)
 mRNAFetal development (T1-2: 10% and T3: 20%)3–12 moIncreased slowlyMethods: PCR, slot blot, RT-PCRYang et al. (1994); Lacroix et al. (1997); Leeder et al. (2005)
CYP3A5
 ProteinFetal development (42%)NR (9 yr: 196%)Inconsistent patternMethods: immunoblotWrighton et al. (1990); Stevens et al. (2003)
 mRNAFetal development (D)NRNRMethods: PCR, Northern blotSchuetz et al. (1994); Yang et al. (1994)
CYP3A7
 Catalytic activityFetal development (T1-2: 915%)NR (3–12 mo: 232%)Decreased progressivelySubstrate: DHEAS. Matrix: microsomes. Methods: radioactivity, HPLCLacroix et al. (1997); Leeder et al. (2005)
 ProteinFetal development (T1-2: 2000%)1–5 yrDecreased progressivelyMethods: Western blot, immunoblotLacroix et al. (1997); Tateishi et al. (1997); Stevens et al. (2003)
 mRNAFetal development (185%)NRNRMethods: PCR, RT-PCR, Northern blotHakkola et al. (1994); Schuetz et al. (1994); Leeder et al. (2005)
  • D, day; ECOD, 7-ethoxycoumarin O-deethylase; HPLC, high-performance LC; ND, not detectable; NR, not reported; PCR, polymerase chain reaction; RT-PCR, reverse-transcriptase polymerase chain reaction.