Age-dependent changes in liver microsomal cytochrome P-450.

Compiled by Andrey L. Sukhodub. All comments are welcomed.

last modified:

CYP P-450

Species

Character of changes observed

Method of estimation used

Ref

IA1

rat

Absent in fetal liver till 14 day of pregnancy

IMA *

[1]

 

 

From 15th day of pregnancy constitutive gene expression and further developmental mRNA accumulation occurs

mRNA

[2]

 

 

Detected at low levels in rats of both sexes at ages 1 week-24 months.

IMA, 6b-testosterone-hydroxylase

[3]

 

 

Remain unchanged in 12-36 months period

IMA

[4]

 

hamster

Peak expression was observed in 6-month old hamsters and declined in older ones

IMA

[44]

 

mouse

In B10.RIII mice progressively decrease between 4 and 28 months; in C57BL/10 mice little or no changes with age

mRNA

[5, 6]

 

rabbit

Absent in embryos, in newborn - low level; sharply accumulates till 1-2 months after birth; maximal level in 2-6 months, then decline

mRNA

[7, 8]

 

man

In adult liver microsomes was not detected. Located in lungs and placenta.

IMA

[9, 35]

 

 

Immunoreactive antibodies detected in fetal liver.

IMA

[39]

IA2

rat

Constitutive level versus total content of P-450 is higher in 1-day then in 15-day rats, but the amount of immunoreactive form is not depends upon age

IMA

[10]

 

 

Detected at low levels in rats of both sexes and ages (1 week-24 months)

IMA, 6b-testosterone-hydroxylase

[3]

 

 

Remains unchanged in the age 12-36 months

IMA, mRNA

[4, 11]

 

hamster

Peak expression was observed in 6-month old hamsters and declined in older ones

IMA

[44]

 

mouse

Decrease between age 4-5 months and 30-31 months

mRNA

[6]

 

rabbit

Present at low level or absent in the new born animal up to week 3, sharply accumulated between weeks 3 and 4 to reach a maximum by week 2. After 2nd month of life begin to fall.

mRNA, IMA

[7, 8, 40]

 

man

Absent in the microsomes from fetal and neonatal livers. Increased in infants aged 1-3 months to attain 50% of the adult value at one year.

IMA, imipramine demethylation, mRNA

[9, 12]

 

 

Unaltered with advancing age. Up to 60-fold variability between livers.

IMA

[13, 35]

 

 

Activity falls in elderly

caffeine clearance

[34]

IB1

man

The level of expression was very low in adult liver and only three out of six fetal livers expressed CYP1B1.

mRNA

[43]

IIA1

rat

The level was maximal at 3 weeks of age in rats of both sexes

IMA, testosterone 7a-hydroxylation

[3, 33]

 

 

In males decrease in postsuckling period

testosterone 7a-hydroxylation

[14, 15]

 

 

The level and activity elevated in the old rats. Female predominant

IMA, mRNA, testosterone 7a-hydroxylation

[16]

IIA2

rat

Detected in male rats only and was induced developmentally. Disappeared at 24 months of age.

IMA, testosterone 15a-hydroxylation

[3]

 

 

Had no changes with aging

IMA

[4]

IIA6

rat

3-week-old rats had the highest activity

coumarin 7-hydroxylation

[34]

 

man

No differences between perinatal and infant and after infancy patients

IMA

[17]

 

 

About 4% of total content. Minor form. Large, (up to 170-fold) variability.

IMA, specific probes

[18, 35]

IIB1/B2

rat

4 fold increase in 24 hours after birth

mRNA

[19]

 

 

Decrease with aging

mRNA

[20]

 

 

Detected at low levels in rats of both sexes at 1 week to 24 months. Had no changes with aging

IMA, testosterone 16b-hydroxylation

[3, 4]

 

hamster

Content reached the maximum at the age of 6 months and maintained almost the same level thereafter (18 month-old)

IMA

[44]

IIB4

rabbit

Developmentally increase in postnatal period till 2 months. In 2-6 months period the level is constant, then decrease

IMA

[7]

IIB6

man

Expressed highly in subjects over 1 year old.

IMA

[17]

 

 

The minor P-450 form (less then 1% of total content)

IMA, specific substrates

[18]

IIC3

rabbit

Increased in postnatal period between 2-3 weeks, then between 1-2 months

IMA

[7]

IIC6

rat

In males appears in a 4 weeks after birth, then permanently increase between 4-12 weeks. In females mRNA discovered in a small amounts on the 2 week, the level increase till 4 weeks old, after 7 weeks begin to fall.

mRNA

[22]

 

 

The amount is equal in male and female liver.

IMA

[3]

 

hamster

Peak expression was observed in 6-month old hamsters and declined in older ones

IMA

[44]

IIC7

rat

Increases gradually over the first 6 weeks of life.

mRNA

[22]

 

 

The content increase from less then 1% in the young (3 weeks old) males and females to 7-14% in adult (6 weeks). Female predominant.

IMA

[23]

IIC8

man

Absent in fetal liver. Appears in a month after birth. Bimodal distribution in the liver.

IMA, mRNA

[12, 24, 35]

IIC9

man

Absent in fetal liver. Appears in a month after birth.

IMA, mRNA

[12, 24]

 

 

Had no changes with age

IMA

[17]

IIC11

rat

Detected in male rats only and induced developmentally. Disappears at 24 months of age.

IMA, testosterone 2a-hydroxylation

[3]

 

 

Dramatic increase at puberty, between 4,5-5,5 weeks of life.

mRNA

[22, 25]

 

hamster

Content reached the maximum at the age 6 month and maintained almost the same level thereafter (18 month-old)

IMA

[44]

IIC12

rat

Female-specific form. Induced developmentally in female rats and was also detected in male rats at 3 weeks and 24 months of age.

testosterone 15a-hydroxylation

[3, 25]

IIC13

rat

The content increase from 1% in 3 weeks animals to 17% in 6 weeks old of total P-450 content. Male predominant.

IMA

[23]

IIC18

man

Absent in fetal liver and appears in 1 months after birth. Polymorphic.

IMA, mRNA

[24, 35]

IIC23

rat

Maximal expression in early neonates and remained quite stable.

mRNA

[26]

IID6

man

Appears soon after birth.

IMA

[9]

 

 

Had no changes with age.

IMA

[17]

 

 

About 2% of the total P-450 content. Polymorphic.

IMA, specific substrates

[18, 35]

IIE1

rat

Had a little volume or absent in fetal liver, increase in a 4 days after birth and remains high during the first 17 days of neonate.

N-nitrosodimethylamine demethylation

[27]

 

 

In postsuckling period decrease more in males then in females. Female predominant.

 

[14]

 

hamster

Peak expression was observed in 6-month old hamsters and declined in older ones

IMA

[44]

 

rabbit

Not detectable until 2 weeks and increase rapidly to approximately twice the adult level at 5 weeks of age.

mRNA

[28]

 

 

Adult age isoform.

 

[7]

 

man

Protein and its associated activity could not be detected in fetal liver and rise during the first few hours following birth independently of the gestational age (between 25-40 weeks). During this period mRNA level remains fairly low. From 1 months to 1 year the protein content gradually increases and is accompanied by the accumulation of mRNA.

IMA, mRNA

[29]

 

 

Present in liver samples from perinatal, infant and 1 year old patients and no differences was observed between these groups.

IMA

[17]

 

 

In fetal liver present a protein immunoreactive with CCYP2E1 antibodies that exhibited a slightly lower molecular weight than that found in adult liver samples..

IMA

[41]

 

 

Negative association between age and protein content.

IMA

[13]

 

 

About 7% from total P-450 content in adult liver. Up to 50-fold variability.

IMA

[18, 35]

IIE2

rabbit

Specific young age isoform

IMA

[7]

 

 

mRNA detectable immediately after birth and reaches slightly greater than the adult level at 2 weeks of age.

mRNA

[28]

IIIA1

rat

The main constitutive male form. 10 fold increase during the first 24 hours after birth.

mRNA

[19, 42]

IIIA2

rat

Constitutively expressed early after birth and characterized by an extinction in the adult females after 3 weeks. In males disappeared when the rats were 24 months of age. In female was detected only at 1 and 3 weeks of age.

IMA, testosterone 6b-hydroxylation, mRNA

[3, 36, 42]

 

hamster

Peak expression was observed in 6-month old hamsters and declined in older ones

IMA

[44]

IIIA3/4

man

Absent in fetal liver

IMA

[30]

 

 

Extremely weak in the fetus and began to raise after birth to reach 30-40% of the adult activity after 1 month. mRNA accumulation displays a similar pattern of evolution. Major P-450 isoform present in the adult liver. Up to 60-fold variability. Constitutive, about 50% of total content.

testosterone 6b-hydroxylation, mRNA, IMA

[31, 9, 35]

IIIA5

man

Detected in statistically higher percentage of children and adolescents (19 years old and under. Detected in 1 of 10 man fetal livers. Polymorphic - present in 27% of population.

IMA

[32]

IIIA6

rabbit

Present at low level in the new born animal up to week 3, sharply accumulated between weeks 3 and 4 to reach maximum by week 4 and decreased in adult.

mRNA

[7, 8]

IIIA7

mice

The mRNA epression could be detected as early as the 15th embryonic day and increased gradually with advancing gestation, but then so after birth. The protein epression was also detectable postnatally and increased.

MRNA, IMA

[38]

 

man

Expressed in the fetal liver. Activity high in the fetal liver and maximal during the first week following birth before to progressively decline and reached a very low level in adult livers.

16a-hydroxylation of dehydroepiandrosterone, IMA

[31, 17]

 

 

Found in all tested samples of fetal liver as in 7 of 13 adult livers. Expressed at similar levels in fetal liver from either gender.

mRNA

[37]

IIIA9

rat

Detected only in adult rats, which a nearly twofold higher expression in females.

mRNA

[36]

IIIA18

rat

Observed before and after puberty at fairly constant

mRNA

[36]

IIIA23

 

levels that were about 20% higher in males than in females

 

 

IVA1

hamster

Level did not change from 3 to 6 months, and then declined to about 40% of the younger level at 12 and 18 months of age.

IMA

[44]

IVA2

rat

Detected in male rats only and was induced developmentally. Disappeared in male at 24 months of age.

IMA

[3]

IVA3

rat

Induced developmentally and detected at similar level in rats of both sexes at age 1 week-2 months.

IMA

[3]

* IMA - immunoanalyse

REFERENCES

1.    Yang H-Y.L., Namkung M.J., Juchau M.R. Immunodetection, immunoinhibition, immunoquantitation and biochemical analyses of cytochrome P450IAI in tissues of the rat conceptus during the progression of organogenesis// Biochem. Pharmacol. - 1989. - 38, N 22. - P. 4027-4036.

2.    Omiecinski C.J., Redlich C.A., Costa P. Induction and developmental expression of cytochrome P450IA1 messenger RNA in rat and man tissues:detection by the polymerase chain reaction// Cancer Res. - 1990. - 50, N 4. - P. 4315-4321.

3.    Imaoka S., Fujita S., Funae Y. Age-dependent expression of cytochrome P450s in rat liver//Biohim. Biophys. Acta - 1991 - 1097, N3. - P. 187-192.

4.    Horbach G.J., Van Asten J.G., Rietjens I.M., Kremers P., Van Bezooijen C.F. The effect of age on inducibility of various types of rat liver cytochrome P450//Xenobiotica - 1992 - 22, N 5. - P. 515-522.

5.    Mote P.L., Grizzle J.M., Walford R.L., Spindler S.R. Age-related down regulation of hepatic cytochrome P1-450, P3-450, catalase and CuZn-superoxide dismutase RNA//Mech. Ageing Dev. - 1990 - 53, N1. - P. 101-110.

6.    Mote P.L., Grizzle J.M., Walford R.L., Spindler S.R. Influence of age and caloric restriction on expression of hepatic genes for xenobiotic and oxygen metabolizing enzymes in the mouse//J. Gerontol. - 1991 - 46, N 3. - B95-B100.

7.    Bonfils C., Combalbert J., Pineau T., Angevin J., Labroque C., Derancourt J., Capony J-P., Maurel P. Ontogenesis of rabbit liver cytochrome P450. Evidence for a cytochrome P450-IIE(3a)-related form prevailing during the post-natal period//Eur. J.Biochem. - 1990 - 188, N 1 - P. 187-194.

8.    Pineau T., Daujat M., Pichard L., Girard F., Angevain J., Bonfils C., Maurel P. Developmental expression of rabbit cytochrome P450 CYP1A1, CYP1A2 and CYP3A6 genes. Effect of weaning and rifampicin//Eur. J.Biochem. - 1991 - 197, N 1 - P. 145-153.

9.    Sonnier M., Cresteil T. Delayed ontogenesis of CYP1A2 in the man liver//Eur. J. Biochem. - 1998 - 251, N 3 - P. 893-898.

10. Rich K.J., Edwards R.J., Foster J.R., Boobis A.R. Ontogeny of expression and inducibility of hepatic cytochrome P450IA2 in the rat and rabbit//Hum. Toxicol. - 1990 - 9, N 5 - P. 330.

11. Horbach G.J.M.J., van Woudenberg A.D., Slater D.M., van Asten J.G., van Bezooijen C.F.A. Age-related changes in the content of cytochrome P450 isozymes and of their mRNAs//Age - 1987 - 10, N 3 - P. 104.

12. Ratenasavanh D., Beaune P., Morel F., Flinois J.P., Guengerih F.P., Guillouzo A. Intralobular distribution and quantitation of cytochrome P450 enzymes in man liver as a function of age// Hepatology - 1991 - 13, N6 - P. 1142-1151.

13. George J., Byth K., Farrell G.C. Age but not gender selectively affects expression of individual cytochrome P450 proteins in man liver// Biochem. Pharmacol. - 1995 - 50, N 5 - P. 727-730.

14. Waxman D.J., Morrissey J.J., Le Blanc G.A. Female-predominant rat hepatic P450 forms j (IIE1) and 3 (IIA1) are under hormonal regulatory controls distinct from those off the sex-specific P450 forms// Endocrinology - 1989 - 124, N 6 - P. 2954-2966.

15. Arlotto M.P., Parkinson A. Identification of cytochrome P450a (P450 IIA1) as the principal testosterone 7a-hydroxylase in rat liver microsomes and its regulation by thyroid hormones// Arh. Biochem. Biophys. - 1989 - 270, N 2 - P. 458-471.

16. Robinson R.C., Nagata K., Gelboin H.V., Rifkind J., Gonzalez F.J., Friedman F.K. Developmental regulation of hepatic testosterone hydroxylases: simultaneous activation and repression of constitutively expressed cytochromes P450 in senescent rats// Arch. Biochem. Biophys. - 1990 - 277, N 1 - P.5 42-46.

17. Tateishi T., Nakura H., Asoh M., Watanabe M., Tanaka M., Kumi T., Takashima S., Imaoka S., Funae Y., Yabusaki Y., Kamataki T., Kobayashi S. A comparison of hepatic cytochrome P450 protein expression between infancy and postinfancy// Life Sci - 1997 - 61, N 26 - P. 2567-2574.

18. Shimada T., Yamazaki H., Mimura M., Inui Y., Guengerich F.P. Interindividual variations in man liver cytochrome P450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians// J. Pharmacol. Exp. Ther. - 1994 - 270, N 1 - P. 414-423.

19. Simmons D.L., Kasper C.B. Quantitation of mRNAs specific for the mixed-function oxidase system in rat liver and extrahepatic tissues during development// Arch. Biochem. Biophys. - 1989 - 271, N 1 - P. 10-20.

20. van Bezooijen R.L., Wang R.K., Lechner M.C., Schmucker D.L. Aging effects on hepatic NADPH cytochrome P450 reductase, CYP2B1&2, and polymeric immunoglobulin receptor mRNAs in male Fischer 344 rats// Exp. Gerontol. - 1994 - 29, N 2 - P. 187-195.

21. Kimura H., Sogawa K., Sakai Y., Fujii-Kuriyama Y. Alternative splicing mechanism in a cytochrome P450 (P450 PB-1) gene generates the two mRNAs coding for protein of different functions// J. Biol. Chem. - 1989 - 264, N 4 - P. 2338-2342.

22. Janeczko R., Waxman D.J., Le Blanc G.A., Morville A., Adesnik M. Hormonal regulation of levels of the messenger RNA encoding hepatic P450 2c (IIC11), a constitutive male-specific form of cytochrome P450// Mol. Endocrinol. - 1990 - 4, N 2 - P. 295-303.

23. Bandiera S., Ryan D.E., Levin W., Thomas P.E. Age- and sex-related expression of cytochromes P450f and P450g in rat liver// Arch. Biochem. and Biophys. - 1986 - 248, N 2 - P. 658-676.

24. Treuler J.M., Gueret G., Cheron G., Sonnier M., Cresteil T. Developmental expression of CYP2C and CYP2C-dependent activities in the man liver: in-vivo/in-vitro correlation and inducibility// Pharmacogenetics - 1997 - 7, N 6 - P. 441-452.

25. Waxman D.J., Dannan G.A., Guengerich F.P. Regulation of rat hepatic cytochrome P450: age-dependent expression, hormonal impriting and xenobiotic inducibility of sex-specific isoenzymes// Biochemistry - 1985 - 24, N 16 - P. 4409-4417.

26. Marie S., Roussel F., Cresteil T. Age- and tissue-dependent expression of CYP2C23 in the rat// Biochim Biophys Acta - 1993 - 1172, N 1-2 - P. 124-130.

27. Hong J., Pan J., Dong Z., Ning S.M., Yang C.S. Regulation of N-nitrosodimethylamine demethylase in rat liver and kidney// Cancer Res. - 1987 - 47, N 11 - P. 5948-5953.

28. Peng H.M., Porter T.D., Ding X.X., Coon M.J. Differences in the developmental expression of rabbit cytochromes P450 2E1 and 2E2// Mol. Pharmacol. - 1991 - 40, N 1 - P. 58-62.

29. Vieira I., Sonnier M., Cresteil T. Developmental expression of CYP2E1 in the man liver. Hypermethylation control of gene expression during the neonatal period// Eur. J. Biochem. - 1996 - 238, N 2 - P. 476-483.

30. Yang H.Y.L., Lee Q.P., Rettie A.E., Juchau M.R. Functional cytochrome P4503A isoforms in man embryonic tissues: expression during oranogenesis// Mol. Pharmacol. - 1994 - 46, N 5 - P. 922-928

31. Lacroix D., Sonnier M., Moncion A., Cheron G., Cresteil T. Expression of CYP3A in the man liver - evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth// Eur. J. Biochem. - 1997 - 247, N 2 - P. 625-634

32. Wrighton S.A., Brian W.R., Sari M.A., Iwasaki M., Guengerich F.P., Raucy J.L., Molowa D.T., Vandenbranden M. Studies on the expression and metabolic capabilities of man liver cytochrome P450 IIIA5 (HLp3)//Mol. Pharmacol. - 1990 - 38, N 2 - P. 207-213

33. Yamazaki H., Mimura M., Sugahara C., Shimada T. Catalytic roles of rat and man cytochrome P450 2A enzymes in testosterone 7 alpha- and coumarin 7-hydroxylations// Biochem. Pharmacol. - 1994 - 48, N 7 - P. 1524-1527

34. Zeeh J., Fuchs L., Bergmann W., Antonin K.H., Degel F., Bieck P., Platt D. Influence of age, frailty and liver function on the pharmacokinetics of brofaromine// Eur. J.Clin. Pharmacol. - 1996 - 49, N 5 - P. 387-391

35. Glaxo Wellcome Pocket Guide to Drug Metabolism. 1st edition, 1995.

36. Mahnke A., Strotkamp D., Roos P.H., Hanstein W.G., Chabot G.G., Nef P. Epression and inducibility of cytochrome P450 3A9 (CUP3A9) and other members of the CYP3A subfamily in rat liver//Arch. Biochem.Biophys. - 1997 - 337, N1 - P. 62-68.

37. Schuetz J. D., Beach D.L., Guzelian P.S. Selective expression of cytochrome P450 CYP3A mRNAs in embryonic and adult man liver// Pharmacogenetics - 1994 - 4, N1- P.11-20.

38. Li Y., Yokoi T., Sasaki M., Hattori K., Katsuki M., Kamataki T. Perinatal expression and inducibility of man CYP3A7 in C57BL/6N transgenic mice// Biochem Biophys Res Commun -1996 - 228, N2 - P. 312-317.

39. Shimada T., Yamazaki H., Mimura M., Wakamiya N., Ueng Y.F., Guengerich F.P., Inui Y. Characterization of microsomal cytochrome P450 enzymes involved in the oxidation of xenobiotic chemicals in man fetal liver and adult lungs// Drug Metab Dispos - 1996 - 24, N5. - P. 515-522.

40. Ding X., Peng H.M., Coon M.J.. Cytochromes P450 NMa, NMb (2G1), and LM4 (1A2) are differentially expressed during development in rabbit olfactory mucosa and liver// Mol Pharmacol. - 1992 - 42, N6 - P. 1027-1032.

41. Carpenter S.P., Lasker J.M., Raucy J.L. Expression, induction, and catalytic activity of the ethanol-inducible cytochrome P450 (CYP2E1) in man fetal liver and hepatocytes// Mol. Pharmacol. - 1996 - 49, N2. - P.260-268.

42. Ribeiro V., Lechner M.C. Cloning and characterization of a novel CYP3A1 allelic variant: analysis of CYP3A1 and CYP3A2 sex-hormone-dependent expression reveals that the CYP3A2 gene is regulated by testosterone// Arch. Biochem. Biophys. - 1992 - 293, N1. - P.147-152

43. Hakkola J., Pasanen M., Pelkonen O., Hukkanen J., Evisalmi S., Anttila S., Rane A., Mantyla M., Purkunen R., Saarikoski S., Tooming M., Raunio H. Expression of CYP1B1 in human adult and fetal tissues and differential inducibility of CYP1B1 and CYP1A1 by Ah receptor ligands in human placenta and cultured cells// Carcinogenesis - 1997 - 18, N2. - P.391-397

44.Takatori A., Akahori M., Kawamura S., Itagaki S., Yoshikava Y. Localization and age-related changes in cytochrome P-450 expression in APA hamster livers//Exp Anim – 2000 – 49(3) – P. 197-203