Expression of Cytochromes P450 in Fetal, Infant, and Juvenile Liver of Cynomolgus Macaques

doi:10.2133/dmpk.DMPK-11-NT-057

Drug Metabolism and Pharmacokinetics

Volume 26, Issue 6, 2011, Pages 621-626

https://doi.org/10.2133/dmpk.DMPK-11-NT-057 Get rights and content

Summary:

Preclinical data of fetal, infant, and juvenile animals are important for the prediction of drug toxicity in fetuses and children. However, expression of drug-metabolizing enzymes, including cytochromes P450 (CYPs), have not been fully investigated in fetal, infant, or juvenile liver of the cynomolgus macaque, an animal species important for preclinical studies. In this study, hepatic expression of 20 cynomolgus macaque CYPs (mfCYPs) in the CYP14 subfamilies that are relevant to drug metabolism was measured in fetuses, infants, and juveniles using DNA microarrays. Expression of most mfCYPs, including those moderately or abundantly expressed in postnatal livers such as mfCYP2A23, mfCYP2A24, mfCYP2B6, mfCYP2C9, mfCYP2C19, mfCYP2C76, mfCYP2D17, mfCYP2E1 mfCYP3A4, and mfCYP3A5, was much less abundant in fetal livers, but increased substantially after birth. In contrast, expression of mfCYP2C8 in fetal livers was not substantially different from postnatal livers. Since human CYP3A7 is expressed more abundantly in fetal livers than in adult livers, mfCYP3A7, an ortholog of human CYP3A7, was analyzed by quantitative polymerase chain reaction. Expression of mfCYP3A7 in fetal livers was much lower than that in postnatal livers, and greatly increased after birth, unlike the expression of human CYP3A7. These results indicate that expression of most mfCYPs examined was low in fetal livers, but increased greatly in postnatal livers, with a few exceptions such as mfCYP2C8.

References (32)

R. Ise et al.
A newly developed DNA microarray is useful to assess induction of cytochromes P450 in cynomolgus monkey
Drug Metab. Pharmacokinet.
(2011)
Y. Uno et al.
Characterization of cynomolgus monkey cytochrome P450 (CYP) cDNAs: Is CYP2C76 the only monkey-specific CYP gene responsible for species differences in drug metabolism?
Arch. Biochem. Biophys.
(2007)
T. Sakuma et al.
Molecular cloning and functional analysis of cynomolgus monkey CYP1A2
Biochem. Pharmacol.
(1998)
Y. Uno et al.
CYP1D1, pseudogenized in human, is expressed and encodes a functional drug-metabolizing enzyme in cynomolgus monkey
Biochem. Pharmacol.
(2011)
S. Gerbal-Chaloin et al.
Transcriptional regulation of CYP2C9 gene
Role of glucocorticoid receptor and constitutive androstane receptor. J. Biol. Chem.
(2002)
M.B. Lewin et al.
Cisapride-induced long QT interval
J. Pediatr.
(1996)
T. Saito et al.
Novel transcriptional regulation of the human CYP3A7 gene by Sp1 and Sp3 through nuclear factor kB-like element
J. Biol. Chem.
(2001)
T. Anderson et al.
Comparative juvenile safety testing of new therapeutic candidates: relevance of laboratory animal data to children
J. Toxicol. Sci.
(2009)
G. Ginsberg et al.
Evaluation of child/adult pharmacokinetic differences from a database derived from the therapeutic drug literature
Toxicol. Sci.
(2002)
S.C. Sim et al.
CYP3A7 protein expression is high in a fraction of adult human livers and partially associated with the CYP3A7*1C allele
Pharmacogenet. Genomics
(2005)

J.C. Stevens et al.

Developmental expression of the major human hepatic CYP3A enzymes

J. Pharmacol. Exp. Ther.

(2003)

J.S. Leeder et al.

Variability of CYP3A7 expression in human fetal liver

J. Pharmacol. Exp. Ther.

(2005)

H.Y. Yang et al.

Functional cytochrome P4503A isoforms in human embryonic tissues: expression during organogenesis

Mol. Pharmacol.

(1994)

D. Lacroix et al.

Expression of CYP3A in the human liver – evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth

Eur. J. Biochem.

(1997)

J.L. Schardein et al.

Species sensitivities and prediction of teratogenic potential

Environ. Health Perspect.

(1985)

Y. Uno et al.

Macaque cytochromes P450: nomenclature, transcript, gene, genomic structure, and function

Drug Metab. Rev.

(2011)

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The cynomolgus macaque has important advantages over the rhesus macaque for use in research that include easier handling based on smaller body size (Rowe, 1996), lower acquisition cost, better availability, and lack of seasonal fertility which may affect experimental outcome (Taylor 2010). These advantages combined with the high level (~93%) of sequence conservation between the cynomolgus macaque and human genome (Ebeling et al. 2011), and physiological similarity with humans, have contributed to the widespread use of cynomolgus macaques for translational studies in research and drug development (Ebeling et al., 2011; Ise et al., 2011). For these studies, cynomolgus macaques are sourced from several different countries including Mauritius, Vietnam, the Philippines, and Indonesia.
The cynomolgus macaque is an important species for preclinical research, however the extent of genetic variation in this population and its similarity to the human population is not well understood. Exome sequencing was conducted for 101 cynomolgus macaques to characterize genetic variation. The variant distribution frequency was 7.81 variants per kilobase across the sequenced regions, with a total of 2,770,009 single nucleotide variants identified from 2,996,041 loci. A large portion (85.6%) had minor allele frequencies greater than 5%. Enriched pathways for genes with high genetic diversity (≥10 variants per kilobase) were those involving signaling peptides and immune response. Compared to human, the variant distribution frequency and nucleotide diversity in the macaque exome was approximately 4 times greater; however the ratio of non-synonymous to synonymous variants was similar (0.735 and 0.831, respectively). Understanding genetic variability in cynomolgus macaques will enable better interpretation and human translation of phenotypic variability in this species.
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Sundareson proposed that PAs may enter the fetal circulation through placental barrier and cause embryo toxicity (Sundareson, 1942), but experimental evidence is still lacking so far. And because of the low expression of CYPs in fetus (Ise et al., 2011; Lacroix et al., 1997), metabolic activation of PAs in fetus remains uncertain. It has been reported that expression of CYP3 A1/2 in female rats is lower than that in males, which possibly leads to sex bias of PA bioactivation, and may contribute to sex difference of PA toxicity in rats (Lin et al., 2003, 2002; Lin et al., 2007).
Pyrrolizidine alkaloids (PAs) are a class of hepatic toxins widely existing in plants. Cytochromes P450 (CYP) mediates PA bioactivation and toxicities in mammals. It has been reported that PAs can induce developmental toxicity, but systematic research is lacking. In this study, we investigated developmental toxicity of monocrotaline (MCT) in rats. Pregnant rats were administered with MCT (20 mg/kg) intragastrically from gestation day 9 to 20, followed by determination of changes in fetal growth, hepatic morphology, serum biochemical indices, and indicators of hepatocytes apoptosis. MCT was found to induce developmental toxicity and fetal hepatotoxicity, particularly in female fetuses. Metabolic activation was also studied by examination of bioactivation efficiency of MCT in fetal liver microsomes, serum MCT, pyrrole-protein adduction derived from MCT, and hepatic CYP3 A expression of fetuses in vivo. Male fetuses showed greater basal MCT bioactivation than that of female fetuses, but continuous exposure to MCT caused a selective CYP3 A induction in female fetuses, which may contribute to the sex difference in MCT-induced developmental toxicity.
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Citation Excerpt :
Similarly, total RNA was extracted from liver samples from cynomolgus macaques (three males and three females from Cambodia, 4–5 years of age, 3–5 kg) and rhesus macaques (three males from China, 7 years of age, weighing 3–5 kg), and was used to isolate FMO cDNAs. Total RNAs previously extracted from livers of 22 prenatal and postnatal cynomolgus macaques (11, 15, or 19 weeks of gestation; 1, 6, 12, and 18 months postnatal; and 3 years of age) [23] were used to analyze gene expression. Microsomes were prepared from liver samples from 30 cynomolgus macaques (15 males and 15 females from Indochina or Indonesia, 4–9 years of age) and 2 rhesus macaques (males from China, 10–11 years of age) as described previously [24].
Flavin-containing monooxygenases (FMOs), drug-metabolizing enzymes essential for the metabolism of endogenous biochemicals and foreign compounds, have been characterized in human (including FMO1-5 and FMO6P), but remain to be investigated in cynomolgus macaque. In this study, cDNAs of cynomolgus FMO1-5 and FMO6 were isolated and characterized. Amino acid sequences of cynomolgus FMO1-5, respectively, shared high sequence identities (94–98%) and were closely clustered in a phylogenetic tree, with human FMO1-5. Eight different transcripts, due to alternative splicing, were isolated for cynomolgus FMO6, which is highly identical (~96%) to human FMO6P. Among the 10 tissue types analyzed, cynomolgus FMO1, FMO2, FMO4, and FMO6 were most abundantly expressed in kidney, while cynomolgus FMO3 and FMO5 were most abundantly expressed in liver. In kidney and liver, the most abundantly expressed cynomolgus FMO genes were FMO1 and FMO3, respectively. Cynomolgus FMO1, FMO2, FMO3, and FMO5 metabolized benzydamine, and FMO1/FMO3 and FMO3 also metabolized methimazole and trimethylamine, respectively. Rates of benzydamine N-oxygenation (catalyzed by FMO3) varied (approximately 20-fold) among the 28 cynomolgus livers and were significantly correlated with FMO3 protein expression, indicating that the inter-animal variations in benzydamine N-oxygenation might be partly accounted for by the variable FMO3 expression. Cynomolgus FMO6 metabolized benzydamine only slightly, but minimal expression of FMO6 in all tissue precludes the importance of FMO6 in drug metabolism, unlike cynomolgus FMO1, FMO2, FMO3, and FMO5 which were all functional. Abundant expression of FMO1 and FMO3 in kidney and liver, respectively, suggest their importance in drug metabolism in cynomolgus macaque, similar to human.
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NoteExpression of Cytochromes P450 in Fetal, Infant, and Juvenile Liver of Cynomolgus Macaques

Summary:

Drug Metab. Pharmacokinet.

Arch. Biochem. Biophys.

Biochem. Pharmacol.

Biochem. Pharmacol.

Role of glucocorticoid receptor and constitutive androstane receptor. J. Biol. Chem.

J. Pediatr.

J. Biol. Chem.

Comparative juvenile safety testing of new therapeutic candidates: relevance of laboratory animal data to children

J. Toxicol. Sci.

Evaluation of child/adult pharmacokinetic differences from a database derived from the therapeutic drug literature

Toxicol. Sci.

CYP3A7 protein expression is high in a fraction of adult human livers and partially associated with the CYP3A7*1C allele

Pharmacogenet. Genomics

Developmental expression of the major human hepatic CYP3A enzymes

J. Pharmacol. Exp. Ther.

Variability of CYP3A7 expression in human fetal liver

J. Pharmacol. Exp. Ther.

Functional cytochrome P4503A isoforms in human embryonic tissues: expression during organogenesis

Mol. Pharmacol.

Expression of CYP3A in the human liver – evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth

Eur. J. Biochem.

Species sensitivities and prediction of teratogenic potential

Environ. Health Perspect.

Macaque cytochromes P450: nomenclature, transcript, gene, genomic structure, and function

Drug Metab. Rev.

Note
Expression of Cytochromes P450 in Fetal, Infant, and Juvenile Liver of Cynomolgus Macaques