Ontogeny profile of hepatic CYP enzymes in rats based on metabolic activity, protein expression and mRNA expression levels
Percentages represent expression/activity relative to adult levels.
| Onset of Activity and/or Expression | Adult Levels Reached | Age-Related Changes in Activity/Expression | Comments | References | |
|---|---|---|---|---|---|
| CYP1A | |||||
| Catalytic activity | 4 days: UD | M: 30 days; F: 30 days (77%) | M: increased progressively; F: increased slowly | Adult age: 56 days. Fetal development–4 days: NR. Substrate: ethoxyresorufin. Strain and sex: Sprague Dawley (M/F). Matrix: liver microsomes. Methods: HPLC | Asaoka et al. (2010) |
| CYP1A1 | |||||
| Catalytic activity | 4 days: 5% | 21 days | Increased progressively | Adult age: 49–60 days. Fetal development–4 days: NR. Substrate: ethoxyresorufin. Strain and sex: Sprague Dawley and Long-Evans (M/F). Matrix: liver microsomes. Methods: HPLC | Gebremichael et al. (1995); Szabo et al. (2009) |
| Protein expression | 7 days: 76% | 21 days | Increased progressively; no changes after 21 days | Fetal development–7 days: NR. Strain and sex: Wistar (M/F). Methods: Western blotting | Imaoka et al., (1991) |
| mRNA expression | Fetal development: >100% | Fetal development | Inconsistent pattern | Adult age: 42 days. Strain and sex: Sprague Dawley (M/F). Methods: qRT-PCR | de Zwart et al. (2008) |
| CYP1A2 | |||||
| Catalytic activity | 5 days: 10% | 21 days | Increased progressively; decreased in elderly (112 days: 70%) | Adult age: 62–65 days. Substrate: methoxyresorufin. Fetal development–1 day: NR. Strain and sex: Sprague Dawley (M). Matrix: liver microsomes. Methods: HPLC | Alcorn et al. (2007) |
| Protein expression | 3 days: 35% | 28 days: 78% | Increased slowly | Adult age: 42–50 days. Fetal development–3 days: NR. Strain and sex: Sprague Dawley (M/F) and Wistar (M/F). Methods: Western blotting | Imaoka et al. (1991); Alcorn et al. (2007) |
| mRNA expression | Fetal: <1% | 11 days | Increased rapidly; peaked at 15 days (300%) | Adult age: 42–112 days. Strain and sex: Sprague Dawley (M/F). Methods: qRT-PCR | de Zwart et al. (2008); Asaoka et al. (2010) |
| CYP1A1/2 | |||||
| Catalytic activity | M: 1 day (40%); F: 1 day (60%) | 18 days | Increased progressively then decreased in elderly | Adult age: 42–50 days. Substrate: ethoxyresorufin. Strain and sex: Sprague Dawley (M/F). Matrix: liver microsomes. Methods: spectrophotometry | de Zwart et al. (2008); McPhail et al. (2016) |
| Protein expression | 5 days: 45% | 21 days | Increased progressively then decreased in elderly | Adult age: 49–50 days. Fetal development–5 days: NR. Strain and sex: Sprague Dawley (M/F). Methods: Western blotting | McPhail et al. (2016) |
| CYP2A | |||||
| Catalytic activity | 4 days: UD | 16 days | Increased rapidly | Adult age: 56 days. Fetal development–4 days: NR. Substrate: testosterone. Strain and sex: Sprague Dawley (M/F). Matrix: liver microsomes. Methods: HPLC | Asaoka et al. (2010) |
| CYP2A1 | |||||
| Catalytic activity | 1 days: 55% | M: 7 days; F: 21 days | Increased rapidly (M); increased progressively (F) | Adult age: 49–65 days. Fetal development–1 days: NR. Substrates: testosterone, androstenedione. Strain and sex: Sprague Dawley and Wistar (M/F). Matrix: liver microsomes. Methods: HPLC | Imaoka et al. (1991); Wright et al. (1997); Cherala et al. (2007) |
| Protein expression | M: 7 days (95%); F: 7 days (40%) | M: 7 days; F: 21 days | M: peaked at 21 days (300%); F: no changes after 21 days | Adult age: 49–50 days. Fetal development–7 days: NR. Strain and sex: Wistar (M/F). Methods: Western blotting | Imaoka et al. (1991) |
| mRNA expression | M: 4 days (100%); F: 4 days (78%) | M: 4 days; F: 16 days | No changes after 4 days | Adult age: 56 days. Fetal development–4 days: NR. Strain and sex: Sprague Dawley (M/F). Methods: qRT-PCR | Asaoka et al. (2010) |
| CYP2A2 | |||||
| Catalytic activity | 7 days: 70% | 21 days: 67% | Increased slowly then decreased in elderly | Adult age: 49–50 days. Fetal development–7 days: NR. Substrate: testosterone. Strain and sex: Wistar (M/F). Matrix: liver microsomes. Methods: HPLC | Imaoka et al. (1991) |
| Protein expression | M: 7 days (30%); F: 7 days (80%) | M: 21 days (30%); F: 21 days (80%) | M: increased slowly; F: increased rapidly | Adult age: 49–50 days. Fetal development–7 days: NR. Strain and sex: Wistar (M/F). Methods: Western blotting | Imaoka et al. (1991) |
| mRNA expression | M: 4 days (<3%); F: 4 days (>200%) | M: 30 days (10%); F: 4 days (>200%) | M: increased slowly; F: no changes after 4 days | Adult age: 56 days. Fetal development–4 days: NR. Strain and sex: Sprague Dawley (M/F). Methods: qRT-PCR | Asaoka et al. (2010) |
| CYP2B | |||||
| Catalytic activity | M: 4 days (20%); F: 4 days (90%) | M: 30 days (80%); F: 4 days (90%) | M: increased slowly; F: increased rapidly | Adult age: 56 days. Fetal development–4 days: NR. Substrate: testosterone. Strain and sex: Sprague Dawley (M/F). Matrix: liver microsomes. Methods: HPLC | Asaoka et al. (2010) |
| CYP2B1 | |||||
| Catalytic activity | M: 7 days (50%); F: 7 days (>100%) | 14 days | Increased rapidly then decreased in elderly | Adult age: 49–50 days. Fetal development–7 days: NR. Substrate: testosterone, pentoxyresorufin. Strain and sex: Sprague Dawley (M) and Wistar (M/F). Matrix: liver microsomes. Methods: HPLC | Imaoka et al. (1991); Gebremichael et al. (1995) |
| Protein expression | M: 7 days (75%); F: 7 days (>120%) | M: 21 days (77%); F: 7 days | M: increased slowly; F: increased rapidly. Decreased in elderly | Adult age: 49–50 days. Fetal development–7 days: NR. Strain and sex: Wistar (M/F). Methods: Western blotting | Imaoka et al. (1991) |
| mRNA expression | M: 4 days (50%); F: 4 days (20%) | 4 days | No changes after 4 days | Adult age: 56 days. Fetal development–4 days: NR. Strain and sex: Sprague Dawley (M/F). Methods: qRT-PCR | Asaoka et al. (2010) |
| CYP2B2 | |||||
| Protein expression | M: 7 days (70%); F: 7 days (40%) | M: 21 days; F: 21 days (80%) | M: increased progressively | Adult age: 49–50 days. Fetal development–7 days: NR. Strain and sex: Wistar (M/F). Methods: Western blotting | Imaoka et al. (1991) |
| mRNA expression | M: 4 days (700%); F: 4 day (280%) | 4 days | Decreased slowly | Adult age: 56 days. Fetal development–4 days: NR. Strain and sex: Sprague Dawley (M/F) and Long-Evans (M). Methods: qRT-PCR | Szabo et al. (2009); Asaoka et al. (2010)) |
| CYP2B1/2 | |||||
| Catalytic activity | Fetal development: <25% | M: 4 days; F: 7 days | Increased rapidly | Adult age: 56 days. Substrate: pentoxyresorufin. Strain and sex: Sprague Dawley (M/F). Matrix: liver microsomes. Methods: spectrophotometry | de Zwart et al. (2008); McPhail et al. (2016) |
| Protein expression | 5 days: 80%–90% | M: 21 days; F: 15 days | Increased progressively | Adult age: 49–50 days. Fetal development–5 days: NR. Strain and sex: Sprague Dawley (M/F). Methods: Western blotting | McPhail et al. (2016) |
| CYP2C | |||||
| Catalytic activity | 4 days: UD | 30 days: 1% | Increased slowly | Adult age: 56 days. Fetal development–4 days: NR. Substrate: testosterone. Strain and sex: Sprague Dawley (M/F). Matrix: liver microsomes. Methods: HPLC | Asaoka et al. (2010) |
| CYP2C6 | |||||
| Catalytic activity | 28 days: 3000% | NR | Decreased after 28 days | Adult age: 63–65 days. Fetal development–28 days: NR. Substrate: testosterone. Strain and sex: Sprague Dawley (F). Matrix: liver microsomes. Methods: HPLC | Cherala et al. (2007) |
| Protein expression | 7 days: <10% | 21 days: 45% | Increased slowly | Adult age: 49 to 50 days. Fetal development–7 days: NR. Strain and sex: Wistar (M/F). Methods: Western blotting | Imaoka et al. (1991) |
| mRNA expression | 4 days: 25%–30% | 30 days | Increased progressively | Adult age: 56 days. Fetal development–4 days: NR. Strain and sex: Sprague Dawley (M/F). Methods: qRT-PCR | Asaoka et al. (2010) |
| CYP2C11 | |||||
| Catalytic activity | M: 7 days (20%); F: 7 days (90%) | M: 28 days; F: 7 days | M: increased progressively; F: increased rapidly | Adult age: 63–65 days. Fetal development–7 days: NR. Substrate: testosterone, androstenedione. Strain and sex: Sprague Dawley and Wistar (M/F). Matrix: liver microsomes. Methods: HPLC | Imaoka et al. (1991); Wright et al. (1997); Cherala et al. (2007) |
| Protein expression | M: 7 days (6%); F: 7 days (100%) | M: 21 days (17%); F: 21 days (90%) | M: increased slowly; F: increased progressively | Adult age: 49–50 days. Fetal development–7 days: NR. Strain and sex: Wistar (M/F). Methods: Western blotting | Imaoka et al. (1991) |
| mRNA expression | 4 days: <1% | 30 days: 14% | Increased slowly | Adult age: 56 days. Fetal development–4 days: NR. Strain and sex: Sprague Dawley (M/F). Methods: qRT-PCR | Asaoka et al. (2010) |
| CYP2C12 | |||||
| Catalytic activity | 1 days: UD | NR | Decreased in elderly (365 days: 85%) | Adult age: 40 days. Fetal development–1 day: NR. Substrate: testosterone. Strain and sex: Wistar (M). Matrix: liver slices. Methods: HPLC | Lupp et al. (2008) |
| Protein expression | M: 7 days (65%); F: 7 days (<4%) | M: 21 days; F: 21 days (16%) | M: increased progressively; F: inconsistent pattern | Adult age: 49–50 days. Fetal development–7 days: NR. Strain and sex: Wistar (M/F). Methods: Western blotting | Imaoka et al. (1991) |
| CYP2D | |||||
| Catalytic activity | 7 days: 75%–80% | 21 days: 75% | Increased slowly | Adult age: 49 days. Fetal development–7 days: NR. Substrate: bufuralol. Strain and sex: Wistar (M/F). Matrix: liver microsomes. Methods: HPLC | Chow et al. (1999) |
| Protein expression | 7 days: 65%–75% | 21 days: 65% | Increased slowly | Adult age: 49 days. Fetal development–7 days: NR. Strain and sex: Wistar (M/F). Methods: immunoblotting | Chow et al. (1999) |
| CYP2D1 | |||||
| mRNA expression | 7 days: >80% | 21 days | Increased progressively then decreased in elderly | Adult age: 49 days. Fetal development–7 days: NR. Strain and sex: Wistar (M/F). Methods: RT-PCR | Chow et al. (1999) |
| CYP2D2 | |||||
| mRNA expression | 7 days: 100% | 7 days | Increased rapidly. No changes after 7 days | Adult age: 49 days. Fetal development–7 days: NR. Strain and sex: Wistar (M/F). Methods: RT-PCR | Chow et al. (1999) |
| CYP2D3 | |||||
| mRNA expression | M: 7 days (15%); F: 7 days (40%) | 21 days: 30%–50% | Increased slowly | Adult age: 49 days. Fetal development–7 days: NR. Strain and sex: Wistar (M/F). Methods: RT-PCR | Chow et al. (1999) |
| CYP2E1 | |||||
| Catalytic activity | M: 1 day (10%); F: 5 days (60%) | 7 days | Increased rapidly | Adult age: 42–50 days. Fetal development–1 day: NR. Substrates: aniline, p-nitro-phenol. Strain and sex: Sprague Dawley (M/F). Matrix: liver microsomes. Methods: spectrophotometry | de Zwart et al. (2008); McPhail et al. (2016) |
| Protein expression | M: 3 days (40%); F: 5 days (180%) | M: 10 days; F: fetal development | M: increased rapidly. F: no changes after 5–10 days | Adult age: 42–112 days. Fetal development–3 days: NR. Strain and sex: Sprague Dawley and Wistar (M/F). Methods: Western blotting | Imaoka et al. (1991); Alcorn et al. (2007); McPhail et al. (2016) |
| mRNA expression | Fetal development (M: 9%, F: 20%) | M: 10 days; F: 7 days | Increased rapidly. Peaked at 15 days (F: 500%) | Adult age: 42–112 days. Strain and sex: Sprague Dawley (M/F). Methods: qRT-PCR | Elbarbry et al. (2007); de Zwart et al. (2008) |
| CYP3A | |||||
| Catalytic activity | 1 days: <10% | M: 21 days; F: 4 days | M: increased progressively. F: increased rapidly. Decreased in elderly | Adult age: 50–65 days. Substrate: testosterone, androstenedione, benzoxyresorufin. Strain and sex: Sprague Dawley and Wistar (M/F) and Long-Evans (M). Matrix: Methods: HPLC | Imaoka et al. (1991); Johnson et al. (2000); Szabo et al. (2009); Asaoka et al. (2010); Wright et al. (2010) |
| Protein expression | M: 1 days (180%); F: 1 days (70%) | M: 1 day; F: 10 days | Increased rapidly | Adult age: 60–63 days. Strain and sex: Wistar (M/F). Methods: Western blotting | Johnson et al. (2000) |
| CYP3A1/2 | |||||
| Catalytic activity | 1 day: <2% | 28 days: 80%–90% | Increased progressively | Adult age: 42 days. Substrate: ethoxyresofurin. Fetal development–1 day: NR. Strain and sex: Sprague Dawley (M/F). Matrix: liver microsomes. Methods: spectrophotometry | de Zwart et al. (2008) |
| CYP3A1 | |||||
| Catalytic activity | NR | NR | Inconsistent pattern | Fetal development–28 days: NR. Substrate: testosterone. Strain and sex: Sprague Dawley (M). Matrix: liver microsomes. Methods: HPLC | Cherala et al. (2007) |
| Protein expression | NR | NR | Decreased in elderly (728 days: 45%) | Adult age: NR. Fetal development–adult: NR. Strain and sex: Fischer-344 (M). Methods: Western blotting | Warrington et al. (2004) |
| mRNA expression | 4 days: 200%–600% | Fetal development | No changes | Adult age: 56–60 days. Strain and sex: Sprague Dawley and Wistar (M/F). Methods: qRT-PCR | Asaoka et al. (2010); Kawase et al. (2015) |
| CYP3A2 | |||||
| Catalytic activity | 1 day: <1% | M: 21 days (75%); F: 7 days | M: increased slowly then decreased in elderly; F: peaked at 7 days (500%) | Fetal development–1 day: NR. Substrate: testosterone. Strain and sex: Wistar (M/F). Matrix: liver microsomes and liver slices. Methods: HPLC | Imaoka et al. (1991); Lupp et al. (2008) |
| Protein expression | M: 7 days (45%); F: 7 days (170%) | M: 21 days (60%); F: 7 days | M: increased slowly then decreased in elderly | Adults age: 42–63 days. Fetal development–7 days: NR. Strain: Fischer-344 (M) and Wistar (M/F). Methods: Western blotting | Imaoka et al. (1991); Warrington et al. (2004) |
| mRNA expression | Fetal development: 30%–1000% | Fetal development or M: 7 days, F: 16 days | Peaked at 16 days or increased rapidly | Adults age: 42–60 days. Strain and sex: Sprague Dawley (M/F). Methods: qRT-PCR | Mahnke et al. (1997); de Zwart et al. (2008) |
| CYP3A9 | |||||
| mRNA expression | 4 days: 20% or 7 days: <3% | M: 30 days (36%); F: 30 days (80%) | Increased slowly | Adult age: 49–56 days. Fetal development–4 days: NR. Strain and sex: Sprague Dawley (M/F). Methods: qRT-PCR | Mahnke et al. (1997); Asaoka et al. (2010) |
| CYP3A11 | |||||
| mRNA expression | Fetal development: <5% | 7 days | Increased rapidly then decreased in elderly | Adult age: 56 days. Strain and sex: Wistar (M). Methods: qRT-PCR | Cuesta de Juan et al. 2007 |
| CYP3A18 | |||||
| mRNA expression | M: 4 days (4%); F: 4 days (78%) | M: NR or 7 days; F: 7–16 days | M: increased slowly or rapidly. F: increased rapidly | Adult age: 49–56 days. Fetal development–4 days: NR. Strain and sex: Sprague Dawley (M/F). Methods: qRT-PCR | Mahnke et al. (1997); Asaoka et al. (2010) |
| CYP3A23 | |||||
| mRNA expression | M: 4 days (20%); F: 4 days (55%) | 7 days | Increased rapidly | Adult age: 49–56 days. Fetal development–4 days: NR. Strain and sex: Sprague Dawley (M/F). Methods: qRT-PCR | Mahnke et al. (1997); Asaoka et al. (2010) |
| CYP4A1 | |||||
| Catalytic activity | Fetal development (M: 70%, F: 190%) | M: 7 days; F: fetal development | Inconsistent pattern | Adult age: 42 days. Substrate: lauric acid. Strain and sex: Sprague Dawley (M/F). Matrix: liver microsomes. Methods: spectrophotometry | de Zwart et al. (2008) |
| mRNA expression | Fetal development: 100% | Fetal development | Inconsistent pattern | Adult age: 42 days. Strain and sex: Sprague Dawley (M/F). Methods: qRT-PCR | de Zwart et al. (2008) |
| CYP4A2 | |||||
| Protein expression | M: 7 days (20%); F: 7 days (100%) | M: 21 days (20%); F: 7 days | M: increased slowly; F: no changes after 7 days | Adult age: 49–50 days. Fetal development–7 days: NR. Strain and sex: Wistar (M/F). Methods: Western blotting | Imaoka et al. (1991) |
| CYP4A3 | |||||
| Protein expression | 7 days: 20%–30% | 21 days: 20%–30% | Increased slowly | Adult age: 49–50 days. Fetal development–7 days: NR. Strain and sex: Wistar (M/F). Methods: Western blotting | Imaoka et al. (1991) |
| CYP7A1 | |||||
| mRNA expression | Fetal development: 30%–130% | Fetal development | Inconsistent pattern | Adult age: 56 days. Strain and sex: Wistar (M). Methods: qRT-PCR | Cuesta de Juan et al. (2007) |
| CYP8B1 | |||||
| mRNA expression | Fetal development: 2%–40% | 1 day | Inconsistent pattern | Adult age: 56 days. Strain and sex: Wistar (M). Methods: qRT-PCR | Cuesta de Juan et al. (2007) |
| CYP27 | |||||
| mRNA expression | Fetal development: 20%–40% | 1 day | Increased rapidly | Adult age: 56 days. Strain and sex: Wistar (M). Methods: qRT-PCR | Cuesta de Juan et al. (2007) |
F, female; HPLC, high-performance LC; M, male; NR, not reported; qRT-PCR, quantitative RT-PCR; RT-PCR, reverse-transcriptase polymerase chain reaction; UD, undetected.