CYP2C8
Cytochrome P450 2C8 (EC 1.14.14.1) (CYPIIC8) (Cytochrome P450 IIC2) (Cytochrome P450 MP-12) (Cytochrome P450 MP-20) (Cytochrome P450 form 1) (S-mephenytoin 4-hydroxylase)
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Whether age and inter-individual variability of pharmacogenetics are risk factors for paclitaxel-induced peripheral neuropathy (PIPN) is inconclusive. This study was conducted to evaluate the influence of previously investigated single nucleotide polymorphisms (SNPs) and age, using genotype data from a prospective study of paclitaxel-related toxicity in Japanese patients with breast cancer. Peripheral blood mononuclear cells from 127 Japanese women with breast cancer who received weekly adjuvant paclitaxel were used to genotypes SLCO1B3 T334G (rs4149117), CYP2C8 A1196G (rs10509681), ABCB1 C1236T (rs1128503), ABCB1 G2677T/A (rs2032582), and ABCB1 C3435T (rs1045642). Genotypic and clinical factors were investigated for associations with PIPN. Of the five SNPs evaluated, no SNPs were significantly associated with grade 2 or higher PIPN. However, ABCB1 1236 TT showed a trend to associate with grade 2 or higher PIPN compared to ABCB1 CT/CC (odds ratio 2.1, 95% CI 0.991-4.548, p = 0.051). In subgroup analysis, patients ≥60 years old with an ABCB1 1236 TT had a higher incidence of ≥grade 2 PIPN compared to patients with CT or CC genotype (p = 0.027). On multivariable analysis, age ≥60 years and the ABCB1 1236 TT showed a significant association with ≥grade 2 PIPN (p = 0.005 and p = 0.034, respectively). ABCB1 1236 TT genotype and older age might be a predictor of PIPN, which diminishes quality of life of cancer survivors.
MeSH Terms
- ATP Binding Cassette Transporter, Subfamily B
- Adult
- Aged
- Aging
- Antineoplastic Agents, Phytogenic
- Asian Continental Ancestry Group
- Breast Neoplasms
- Cytochrome P-450 CYP2C8
- Female
- Genotype
- Humans
- Incidence
- Middle Aged
- Organic Anion Transporters, Sodium-Independent
- Paclitaxel
- Peripheral Nervous System Diseases
- Pharmacogenetics
- Polymorphism, Single Nucleotide
- Predictive Value of Tests
- Prospective Studies
- Sensory Receptor Cells
- Solute Carrier Organic Anion Transporter Family Member 1B3
Keywords
- ABCB1
- CYP2C8
- Older age
- Paclitaxel-induced peripheral neuropathy
- SLCO1B3
Predicting age-specific metabolism is important for evaluating age-related drug and chemical sensitivity. Multiple cytochrome P450s and carboxylesterase enzymes are responsible for human pyrethroid metabolism. Complete ontogeny data for each enzyme are needed to support in vitro to in vivo extrapolation (IVIVE). This study was designed to determine age-dependent human hepatic CYP2C8 expression, for which only limited ontogeny data are available, and to further define CYP1A2 ontogeny. CYP2C8 and 1A2 protein levels were measured by quantitative Western blotting using liver microsomal samples prepared from 222 subjects with ages ranging from 8 weeks gestation to 18 years after birth. The median CYP2C8 expression was significantly greater among samples from subjects older than 35 postnatal days ([i]n =[/i] 122) compared with fetal samples and those from very young infants (fetal to 35 days postnatal, [i]n =[/i] 100) (0.00 vs. 13.38 pmol/mg microsomal protein; [i]p[/i] < 0.0001). In contrast, the median CYP1A2 expression was significantly greater after 15 months postnatal age ([i]n =[/i] 55) than in fetal and younger postnatal samples (fetal to 15 months postnatal, [i]n =[/i] 167) (0.0167 vs. 2.354 pmol/mg microsomal protein; [i]p[/i] < 0.0001). CYP2C8, but not CYP1A2, protein levels significantly correlated with those of CYP2C9, CYP2C19, and CYP3A4 ([i]p[/i] < 0.001), consistent with CYP2C8 and CYP1A2 ontogeny probably being controlled by different mechanisms. This study provides key data for the physiologically based pharmacokinetic model-based prediction of age-dependent pyrethroid metabolism, which will be used for IVIVE to support pyrethroid risk assessment for early life stages.
MeSH Terms
- Adolescent
- Adult
- Aging
- Child
- Child, Preschool
- Cytochrome P-450 CYP1A2
- Cytochrome P-450 CYP2C8
- Female
- Fetal Development
- Gene Expression
- Gene Ontology
- Gestational Age
- Humans
- In Vitro Techniques
- Infant
- Infant, Newborn
- Liver
- Male
- Microsomes, Liver
- Risk Assessment
- Xenobiotics
- Young Adult
Apixaban is an oral, direct, and highly selective factor Xa inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. The metabolic drug-drug interaction potential of apixaban was evaluated in vitro. The compound did not show cytochrome P450 inhibition (IC(50) values >20 microM) in incubations of human liver microsomes with the probe substrates of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Apixaban did not show any effect at concentrations up to 20 muM on enzyme activities or mRNA levels of selected P450 enzymes (CYP1A2, 2B6, and 3A4/5) that are sensitive to induction in incubations with primary human hepatocytes. Apixaban showed a slow metabolic turnover in incubations of human liver microsomes with formation of O-demethylation (M2) and hydroxylation products (M4 and M7) as prominent in vitro metabolites. Experiments with human cDNA-expressed P450 enzymes and P450 chemical inhibitors and correlation with P450 activities in individual human liver microsomes demonstrated that the oxidative metabolism of apixaban for formation of all metabolites was predominantly catalyzed by CYP3A4/5 with a minor contribution of CYP1A2 and CYP2J2 for formation of M2. The contribution of CYP2C8, 2C9, and 2C19 to metabolism of apixaban was less significant. In addition, a human absorption, distribution, metabolism, and excretion study showed that more than half of the dose was excreted as unchanged parent (f(m CYP) <0.5), thus significantly reducing the overall metabolic drug-drug interaction potential of apixaban. Together with a low clinical efficacious concentration and multiple clearance pathways, these results demonstrate that the metabolic drug-drug interaction potential between apixaban and coadministered drugs is low.
MeSH Terms
- Aging
- Anticoagulants
- Cells, Cultured
- Cytochrome P-450 CYP3A
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Enzyme System
- Drug Evaluation, Preclinical
- Drug Interactions
- Factor Xa Inhibitors
- Hepatocytes
- Humans
- Hydroxylation
- Isoenzymes
- Kinetics
- Metabolic Detoxication, Phase I
- Microsomes
- Organ Specificity
- Pyrazoles
- Pyridones
- RNA, Messenger
- Recombinant Proteins
We have measured cytochrome P450 (CYP) activity in nearly 150 samples of human liver microsomes and 64 samples of cryopreserved human hepatocytes, and we have performed induction studies in over 90 preparations of cultured human hepatocytes. We have analyzed these data to examine whether the expression of CYP enzyme activity in liver microsomes and isolated hepatocytes or the inducibility of CYP enzymes in cultured hepatocytes is influenced by the gender, age, or ethnicity of the donor (the latter being limited to Caucasians, African Americans, and Hispanics due to a paucity of livers from Asian donors). In human liver microsomes, there were no statistically significant differences (P > 0.05) in CYP activity as a function of age, gender, or ethnicity with one exception. 7-Ethoxyresorufin O-dealkylase (CYP1A2) activity was greater in males than females, which is consistent with clinical observation. Liver microsomal testosterone 6beta-hydroxylase (CYP3A4) activity was slightly greater in females than males, but the difference was not significant. However, in cryopreserved human hepatocytes, the gender difference in CYP3A4 activity (females = twice males) did reach statistical significance, which supports the clinical observation that females metabolize certain CYP3A4 substrates faster than do males. Compared with those from Caucasians and African Americans, liver microsomes from Hispanics had about twice the average activity of CYP2A6, CYP2B6, and CYP2C8 and half the activity of CYP1A2, although this apparent ethnic difference may be a consequence of the relatively low number of Hispanic donors. Primary cultures of hepatocytes were treated with beta-naphthoflavone, an inducer of CYP1A2, phenobarbital or rifampin, both of which induce CYP2B6, CYP2C9, CYP2C19, and CYP3A4, albeit it to different extents. Induction of these CYP enzymes in freshly cultured hepatocytes did not appear to be influenced by the gender or age of the donor. Furthermore, CYP3A4 induction in hepatocytes isolated from cirrhotic liver was comparable to that in normal hepatocytes, which supports the "healthy hepatocyte, sick environment" hypothesis of liver cirrhosis. This review summarizes these findings and discusses their implications for the use of human liver microsomes and hepatocytes for in vitro studies of drug metabolism and enzyme induction, which play a key role in drug development.
MeSH Terms
- Aging
- Alcohol Drinking
- Animals
- Cells, Cultured
- Cytochrome P-450 Enzyme System
- Enzyme Induction
- Ethnic Groups
- Female
- Hepatocytes
- Humans
- Isoenzymes
- Liver Cirrhosis
- Male
- Microsomes, Liver
- Sex Characteristics
- Smoking
Experiments were performed in vivo and in vitro to date the onset of hepatic CYP2C isoforms and CYP2C-dependent activities during the perinatal period in humans. Proteins were not detected by immunoblotting in fetal livers and developed in the first few weeks after birth, irrespective of the gestational age at birth. Similarly, the hydroxylation of tolbutamide, a marker for CYP2C9 was undetected in fetal liver microsomes and rose in the first month after birth. In adult liver preparations, the hydroxylation of diazepam correlated well with the CYP3 A content of microsomes (r = 0.858, p < 0.01) and with the 6 beta hydroxylation of testosterone (r = 0.830, p < 0.005), whereas demethylation was related to the bulk of CYP2C proteins (r = 0.865, p < 0.005). In fetal liver microsomes, hydroxylation and demethylation activities accounted for less than 5% of the adult activities and both increased immediately after birth to reach adult activities at 1 year of age. When diazepam was given for sedative purpose in neonates and infants, the in-vivo urinary excretion of desmethyl diazepam, temazepam and oxazepam was extremely low in 1-2 day newborns (less than 5 nmol metabolites excreted in 24 h per kg body weight) and developed in the first week after birth. In newborns, barbiturates and to a lesser extent steroids, acted as inducers of CYP2C isoforms and increased tolbutamide hydroxylation, diazepam demethylation and diazepam hydroxylation by 2 to 10-fold. The surge of CYP2C proteins was caused by an accumulation of RNAs occurring in the first week after birth. The hepatic content in CYP2C8, 2C9 and 2C18 RNA displayed the same profile of evolution, which suggested a coregulation of their synthesis during the neonatal period. Taken together, these biochemical and clinical data enable dating of the onset of CYP2C proteins to the first weeks after birth, which is of considerable clinical importance in pediatric pharmacology.
MeSH Terms
- Adult
- Aging
- Child, Preschool
- Cytochrome P-450 Enzyme System
- Diazepam
- Enzyme Induction
- Female
- Fetus
- Gestational Age
- Humans
- Hydroxylation
- Infant
- Infant, Newborn
- Microsomes, Liver
- RNA
- Tolbutamide