A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

Aim:

To develop a pharmacokinetic/pharmacodynamic (PK/PD) model describing the receptor/gene-mediated induction of CYP3A1/2 by dexamethasone (DEX) in rats.

Methods:

A group of male Sprague-Dawley rats receiving DEX (100 mg/kg, ip) were sacrificed at various time points up to 60 h post-treatment. Their blood sample and liver were collected. The plasma concentration of DEX was determined with a reverse phase HPLC method. CYP3A1/2 mRNA, protein levels and enzyme activity were measured using RT-PCR, ELISA and the testosterone substrate assay, respectively. Data analyses were performed using a first-order conditional estimate (FOCE) with INTERACTION method in NONMEM version 7.1.2.

Results:

A two-compartment model with zero-order absorption was applied to describe the pharmacokinetic characteristics of DEX. Systemic clearance, the apparent volume of distribution and the duration of zero-order absorption were calculated to be 172.7 mL·kg⁻¹·h⁻¹, 657.4 mL/kg and 10.47 h, respectively. An indirect response model with a series of transit compartments was developed to describe the induction of CYP3A1/2 via PXR transactivation by DEX. The maximum induction of CYP3A1 and CYP3A2 mRNA levels was achieved, showing nearly 21.29- and 8.67-fold increases relative to the basal levels, respectively. The CYP3A1 and CYP3A2 protein levels were increased by 8.02-fold and 2.49-fold, respectively. The total enzyme activities of CYP3A1/2 were shown to increase by up to 2.79-fold, with a lag time of 40 h from the Tmax of the DEX plasma concentration. The final PK/PD model was able to recapitulate the delayed induction of CYP3A1/2 mRNA, protein and enzyme activity by DEX.

Conclusion:

A mechanism-based PK/PD model was developed to characterize the complex concentration-induction response relationship between DEX and CYP3A1/2 and to resolve the drug- and system-specific PK/PD parameters for the course of induction.     

The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine

Aims Clozapine (CLZ), an atypical neuroleptic with a high risk of causing agranulocytosis, is metabolized in the liver to desmethylclozapine (DCLZ) and clozapine N-oxide (CLZ-NO). This study investigated the involvement of different CYP isoforms in the formation of these two metabolites. Methods Human liver microsomal incubations, chemical inhibitors, specific antibodies, and different cytochrome P450 expression systems were used. Results K_m and V_max values determined in human liver microsomes were lower for the demethylation (61±21 μm, 159±42 pmol min⁻¹ mg protein⁻¹ mean±s.d.; n=4), than for the N-oxidation of CLZ (308±1.5 μm, 456±167pmol min⁻¹ mg protein⁻¹; n=3). Formation of DCLZ was inhibited by fluvoxamine (53±28% at 10 μm ), triacetyloleandomycin (33±15% at 10 μm ), and ketoconazole (51±28% at 2 μm ) and by antibodies against CYP1A2 and CYP3A4. CLZ-NO formation was inhibited by triacetyloleandomycin (34±16% at 10 μm ) and ketoconazole (51±13% at 2 μm ), and by antibodies against CYP3A4. There was a significant correlation between CYP3A content and DCLZ formation in microsomes from 15 human livers (r=0.67; P=0.04). A high but not significant correlation coefficient was found for CYP3A content and CLZ-NO formation (r=0.59; P=0.09). Using expression systems it was shown that CYP1A2 and CYP3A4 formed DCLZ and CLZ-NO. K_m and V_max values were lower in the CYP1A2 expression system compared to CYP3A4 for both metabolic reactions. Conclusions It is concluded that CYP1A2 and CYP3A4 are involved in the demethylation of CLZ and CYP3A4 in the N-oxidation of CLZ. Close monitoring of CLZ plasma levels is recommended in patients treated at the same time with other drugs affecting these two enzymes.     

Human PXR-mediated transcriptional activation of CYP3A4 by ‘Fuzi’ extracts

Objective: This study focused on determining whether the ‘Fuzi’ (FZ) extracts from different extraction methods are related to pregnane X receptor (PXR) and cytochrome P450 3A4 (CYP3A4), and explore the mechanism.

Methods: FZ was extracted under various conditions, and the components were identified by Ultra Performance Liquid Chromatography/Quad Time of Flight Mass Spectrometry (UPLC/Q-TOF-MS). Annexin V-FITC and propidium iodide staining assays were used to measure the cell cytotoxicity of these extracts. Real-time PCR, western blot analysis and reporter gene assay were used to detect the expression changes of PXR and CYP3A4.

Results: FZ extracts were found to contain high levels of monoester-diterpene alkaloids (MDAs) and diester-diterpene alkaloids (DDAs). FZ extracts were cytotoxic. Interestingly, we found that FZ extracts and DDAs can induce the expressions of PXR and CYP3A4. And the MDAs can inhibit the expressions of PXR and CYP3A4.

Conclusion: Different extracts of FZ can induce the expressions of PXR and CYP3A4 in different degrees. This may be related to the drug-drug interactions.     

CYP3A4高表达细胞模型及其应用于药物代谢研究进展

细胞色素P450酶3A4(cytochrome P450 3A4,CYP3A4)属于细胞色素P450酶家族,参与多种化合物代谢及相互作用,是药物(尤其是口服药物)筛选和代谢研究的重要对象。该文按年代顺序对国外文献中CYP3A4高表达细胞模型的建立及在药物代谢中的应用进行综述,旨在将这一有价值的模型引入到新药研究中。     

中药止咳橘红颗粒对CYP3A4和CYP1A2抑制作用的研究

目的：在人体内研究止咳橘红对CYP3A4和CYP1A2的抑制作用，以预测止咳橘红与常用临床药物的相互作用。方法：咪哒唑仑和咖啡因分别作为CYP3A4和A2的探针药物，采取交叉设计，10名受试者在服用3d止咳橘红的前后均服用7.5mg咪哒唑仑和100mg咖啡因，服药后采血测定两者及代谢产物的代谢动力学参数，探讨针药物及代谢物的浓度用HPLC-MS法测定，Cmax,tmax从药时曲线中直接读出，AUC用梯形法计算，Ke用3P87程序进行拟合计算，分析服药前后CYP3A4和CYP1A2被抑制的情况，结果 服用止咳橘红后，咪哒唑仑的代谢受到了轻微的抑制，它的血药浓度，达峰时间和药时曲线下面积都有了升高趋势，但无显著差异。而咖啡因的代谢未受到影响。结论 止咳橘红对CYP3A4的活性有较弱的抑制作用，能够导致CYP3A4底物咪哒唑仑代谢的轻微抑制，而对CYP1A2的活性没有影响。止咳橘红长期使用或超过治疗剂量使用时是否会对CYP3A4产生显著性影响。尚需进一步的研究证明。     

Comparative analysis of substrate and inhibitor interactions with CYP3A4 and CYP3A5

To evaluate the role that cytochrome (CYP) 3A5 plays in hepatic drug metabolism, the substrate selectivity and inhibitory potential of over 60 compounds towards CYP3A4 and CYP3A5 were assessed using Escherichia coli recombinant cell lines. CYP3A4-mediated metabolism predominated for many of the compounds studied. However, a number of drugs gave similar CL_int estimates using CYP3A5 compared with CYP3A4 including midazolam (CL_int?=?3.4 versus 3.3?µl?min^–1?pmol^–1). Significant CYP3A5-mediated metabolism was also observed for several drugs including mifepristone (CL_int?=?10.3 versus 2.4?µl?min^–1?pmol^–1), and ritonavir (CL_int?=?0.76 versus 0.47?µl?min^–1?pmol^–1). The majority of compounds studied showed a greater inhibitory potential (IC₅₀) towards CYP3A4 compared with CYP3A5 (eightfold lower on average). A greater degree of time-dependent inhibition was also observed with CYP3A4 compared with CYP3A5. The range of compounds investigated in the present study extends significantly previous work and suggests that CYP3A5 may have a significant role in drug metabolism particularly in populations expressing high levels of CYP3A5 and/or on co-medications known to inhibit CYP3A4.     

IC50-based approaches as an alternative method for assessment of time-dependent inhibition of CYP3A4

1. The predictive utility of two in vitro methods (empirical IC₅₀-based and mechanistic k_inact/K_I) for the assessment of time-dependent cytochrome P450 3A4 (CYP3A4) inhibition has been compared.

2. IC₅₀ values were determined at multiple pre-incubation time points over 30?min for five CYP3A4 time-dependent inhibitors (verapamil, diltiazem, erythromycin, clarithromycin, and azithromycin). The ability of IC₅₀ data obtained following pre-incubation to predict k_inact/K_I parameters was investigated and its utility was assessed relative to the conventional k_inact/K_I model using 50 reported clinical drug–drug interactions (DDIs). Models with either hepatic or hepatic with intestinal components were explored.

3. For low/medium potency time-dependent inhibitors, 81% of the predicted k_inact/K_I(unbound) from IC₅₀ data were within an order of magnitude of the actual values, in contrast to 50% of potent inhibitors. An underprediction trend and >?50% of false-negatives were observed when IC₅₀ data were used in the DDI hepatic prediction model; incorporation of the intestine improved the prediction accuracy. On the contrary, 86% of the DDI studies were predicted within twofold using k_inact/K_I mechanistic approach and the combined hepatic and intestinal model.

4. Use of the empirical IC₅₀ approach as an alternative to the mechanistic k_inact/K_I model for in vivo DDI prediction is limited and is best restricted to preliminary investigations.

     

Effects of CYP3A4 inhibition and induction on the pharmacokinetics and pharmacodynamics of tolvaptan, a non-peptide AVP antagonist in healthy subjects

AIMS

In vitro studies indicated CYP3A4 alone was responsible for tolvaptan metabolism. To determine the effect of a CYP3A4 inhibitor (ketoconazole) and a CYP3A4 inducer (rifampicin) on tolvaptan pharmacokinetics (PK) and pharmacodynamics (PD), two clinical trials were performed.

METHODS

For CYP3A4 inhibition, a double-blind, randomized (5:1), placebo-controlled trial was conducted in 24 healthy subjects given either a single 30 mg dose of tolvaptan (n = 19) or matching placebo (n = 5) on day 1 with a 72 h washout followed by a 3 day regimen of 200 mg ketoconazole, once daily with 30 mg tolvaptan or placebo also given on day 5. For CYP3A4 induction, 14 healthy subjects were given a single dose of 240 mg tolvaptan with 48 h washout followed by a 7 day regimen of 600 mg rifampicin, once daily, with 240 mg tolvaptan also given on the seventh day.

RESULTS

When co-administered with ketoconazole, mean C_max and AUC(0,∞) of tolvaptan were increased 3.48- and 5.40-fold, respectively. Twenty-four hour urine volume increased from 5.9 to 7.7 l. Erythromycin breath testing showed no difference following a single dose of tolvaptan. With rifampicin, tolvaptan mean C_max and AUC were reduced to 0.13- and 0.17-fold of tolvaptan administered alone. Twenty-four hour urine volume decreased from 12.3 to 8.8 l.

CONCLUSIONS

Tolvaptan is a sensitive CYP3A4 substrate with no inhibitory activity. Due to the saturable nature of tolvaptan''s effect on urine excretion rate, changes in the pharmacokinetic profile of tolvaptan do not produce proportional changes in urine output.     

三氯乙烯对3种细胞色素P450酶基因表达的影响

目的 探讨三氯乙烯（Trichloroethylene,TCE)对人体淋巴细胞瘤细胞株（MCL-5）中3种细胞色素P450酶基因（CYP1A1、CYP2E1、CYP3A4）表达的影响,并研究剂量反应关系和时间反应关系,方法 用常规的细胞培养方法,0.5、1.0、1.5、2.0mmol/L TCE处理细胞12、24、48、72h。利用提纯RNA和cDNA的药盒,合成cDNA,然后逆转录聚合酶反应（RT-PCR）表达3种CYP450基因,以β-Actin作为内对照,分析不同处理剂量和时间时基因表达的强度。结果 在MCL-5细胞株中都有基本的表达,CYP1A1表达在用1.0、1.5、2.0mmol/LTCE处理48h后有被上调的趋势,而且上调趋势随处理时间延长耐加强;CYP2E1、CYP3A4表达不受TCE处理时间长短的影响。3种CYP450酶基因的表达受TCE剂量的影响。3随0.5mol/L,1.0、1.5、2.0mmol/L剂量的增加有上调的趋势,结论 TCE对CYP450酶系统中的CYP2E1、CYP1A1、CYP3A4基因有明显的诱导作用。这些基因被诱导后的结果。可能会导致相对应酶活性的增加,同时加强对TCE的代谢,使TCE的代谢产物增加。     

In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors

Objective: The affinity of (+)-, (−)- and (±)-fluvastatin, a new synthetic HMG-CoA reductase inhibitor developed as a racemate, for specific human P450 monooxygenases in liver microsomes was compared with that of the pharmacologically active acidic forms of lovastatin, pravastatin and simvastatin. Methods: Affinity was determined as the inhibitory potency for prototype reactions for 3 major drug metabolising enzymes: diclofenac 4′-hydroxylation (CYP2C9), dextromethorphan O-demethylation (CYP2D6), and midazolam 1′-hydroxylation (CYP3A4). Results: Lovastatin acid, pravastatin and simvastatin acid displayed moderate affinity for all three P450 isozymes (estimated K_i > 50 μmol⋅l⁻¹). Racemic and (+)- and (−)-fluvastatin showed moderate affinity (estimated K_i > 50 μmol⋅l⁻¹) for CYP2D6 and CYP3A4, whereas their affinity for CYP2C9 was high (estimated K_i < 1 μmol⋅l⁻¹). Diclofenac 4′-hydroxylation was competitively and stereoselectively inhibited, with measured K_i’s of 0.06 and 0.28 μmol⋅l⁻¹ for (+)- and (−)-fluvastatin, respectively. Conclusion: Fluvastatin selectively inhibits a major drug metabolising enzyme (CYP2C9), the (+)-isomer (pharmacologically more active) showing 4–5 fold higher affinity. As already reported for lovastatin and simvastatin, in vivo drug interactions by inhibition of liver oxidation of CYP2C9 substrates (e.g. hypoglyceamic sulphonylureas and oral anticoagulants) may be expected. Received: 9 June 1995/Accepted in revised form: 7 November 1995     

A clinical study to assess CYP1A2 and CYP3A4 induction by AZD7325, a selective GABA(A) receptor modulator - an in vitro and in vivo comparison

AIM(S)

To investigate the potential of AZD7325 to induce CYP1A2 and CYP3A4 enzyme activities.

METHODS

Induction of CYP1A2 and CYP3A4 by AZD7325 was first evaluated using cultured human hepatocytes. The effect of multiple doses of 10 mg AZD7325 on the pharmacokinetics of midazolam and caffeine was then examined in healthy subjects.

RESULTS

The highest CYP1A2 and CYP3A4 induction responses were observed in human hepatocytes treated with 1 or 10 µm of AZD7325, in the range of 17.9%–54.9% and 76.9%–85.7% of the positive control responses, respectively. The results triggered the further clinical evaluation of AZD7325 induction potential. AZD7325 reached a plasma C_max of 0.2 µm after 10 mg daily dosing to steady-state. AZD7325 decreased midazolam geometric mean AUC by 19% (0.81-fold, 90% CI 0.77, 0.87), but had no effect on midazolam C_max (90% CI 0.82, 0.97). The mean CL/F of midazolam increased from 62 l h⁻¹ (midazolam alone) to 76 l h⁻¹ when co-administered with AZD7325. The AUC and C_max of caffeine were not changed after co-administration of AZD7325, with geometric mean ratios (90% CI) of 1.17 (1.12, 1.23) and 0.99 (0.95, 1.03), respectively.

CONCLUSIONS

While AZD7325 appeared to be a potent CYP3A4 inducer and a moderate CYP1A2 inducer from in vitro studies, the expected efficacious dose of AZD7325 had no effect on CYP1A2 activity and only a weak inducing effect on CYP3A4 activity. This comparison of in vitro and in vivo results demonstrates the critical role that clinical exposure plays in evaluating the CYP induction risk of a drug candidate.     

A reporter gene cellular model for evaluating induction of CYP3A4 by new chemical entities

A cell‐based reporter gene assay to study CYP3A4 induction was developed in the present study. The pregnane X receptor (PXR) gene or variant (PXR2) was cloned into the pSG5 vector and cotransfected into HepG2 cells, with a construct, pGL3‐3A4‐Luc, containing the promoter/enhancer region of the CYP3A4 gene. The two systems were validated using rifampicin (RIF). The variant, PXR2, did not mediate induction of CYP3A4 by rifampicin (10 µM) whereas PXR showed dose‐dependent induction of CYP3A4, with a fold change of 40–60, compared to the vehicle control, 0.1% dimethylsulfoxide (DMSO). Further validation of the PXR/3A4 system was performed using other inducers of CYP3A4, after which CYP3A4 inducibility by a Wyeth compound, Tanaproget (TNPR), and the synthetic steroid, 3‐ketodesogestrel (3‐KDG), were assessed. At the highest concentrations tested, troleandomycin (TROL) and phenobarbital (PB) induced CYP3A4 by 15–25‐fold, while carbamazepine (CMZ), dexamethasone (DEX), and erythromycin (ERY) produced fold induction of <3. Pregnenolone 16‐α carbonitrile (PCN), a rat‐specific CYP3A inducer, did not induce CYP3A4. TNPR did not induce CYP3A4 at concentrations up to 10 µM while 3‐KDG produced a concentration‐dependent induction, with a fold change of 14 at 20 µM. These data show that the variant PXR2 is not activated by rifampicin. The PXR/3A4 system described can be used to study CYP3A4 induction and provides a robust, specific, and reproducible in vitro system that can be used to assess CYP3A4 inducibility by compounds in the drug development process. Drug Dev. Res. 67:470–475, 2006. © 2006 Wiley‐Liss, Inc.     

Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates

BACKGROUND AND PURPOSE

Imatinib, a cytochrome P450 2C8 (CYP2C8) and CYP3A4 substrate, markedly increases plasma concentrations of the CYP3A4/5 substrate simvastatin and reduces hepatic CYP3A4/5 activity in humans. Because competitive inhibition of CYP3A4/5 does not explain these in vivo interactions, we investigated the reversible and time-dependent inhibitory effects of imatinib and its main metabolite N-desmethylimatinib on CYP2C8 and CYP3A4/5 in vitro.

EXPERIMENTAL APPROACH

Amodiaquine N-deethylation and midazolam 1′-hydroxylation were used as marker reactions for CYP2C8 and CYP3A4/5 activity. Direct, IC₅₀-shift, and time-dependent inhibition were assessed with human liver microsomes.

KEY RESULTS

Inhibition of CYP3A4 activity by imatinib was pre-incubation time-, concentration- and NADPH-dependent, and the time-dependent inactivation variables K_I and k_inact were 14.3 µM and 0.072 min⁻¹ respectively. In direct inhibition experiments, imatinib and N-desmethylimatinib inhibited amodiaquine N-deethylation with a K_i of 8.4 and 12.8 µM, respectively, and midazolam 1′-hydroxylation with a K_i of 23.3 and 18.1 µM respectively. The time-dependent inhibition effect of imatinib was predicted to cause up to 90% inhibition of hepatic CYP3A4 activity with clinically relevant imatinib concentrations, whereas the direct inhibition was predicted to be negligible in vivo.

CONCLUSIONS AND IMPLICATIONS

Imatinib is a potent mechanism-based inhibitor of CYP3A4 in vitro and this finding explains the imatinib–simvastatin interaction and suggests that imatinib could markedly increase plasma concentrations of other CYP3A4 substrates. Our results also suggest a possibility of autoinhibition of CYP3A4-mediated imatinib metabolism leading to a less significant role for CYP3A4 in imatinib biotransformation in vivo than previously proposed.     

复方银杏叶胶囊对肝损伤大鼠CYP2E1、CYP3A4的影响

目的研究复方银杏叶胶囊(CGB)对酒精性肝损伤大鼠CYP2E1、CYP3A4活性的影响。方法正常组和酒精性肝损伤模型组均以CGB[(250 mg/(kg.d)]灌胃,分别在灌胃CGB前及灌胃1周后,灌胃探针药氯唑沙宗(50 mg/kg)及氨苯砜(20 mg/kg),于探针药灌后24 h内不同时间点采血,测定各探针药血药浓度。结果灌胃CGB前,模型组氯唑沙宗和氨苯砜的AUC0-24、Cmax均显著低于正常组(P<0.05或P<0.01)。灌胃CGB后,模型组氯唑沙宗和氨苯砜的AUC0-24、Cmax均较灌胃前显著升高(P<0.05或P<0.01);且氯唑沙宗的t1/2灌胃CGB后明显高于灌胃前(P<0.05)。结论 CGB能够明显抑制酒精性肝损伤大鼠CYP2E1、CYP3A4酶活性。     

Endosulfan induces CYP2B6 and CYP3A4 by activating the pregnane X receptor

Endosulfan is an organochlorine pesticide commonly used in agriculture. Endosulfan has affects on vertebrate xenobiotic metabolism pathways that may be mediated, in part, by its ability to activate the pregnane X receptor (PXR) and/or the constitutive androstane receptor (CAR) which can elevate expression of cytochrome P450 (CYP) enzymes. This study examined the dose-dependency and receptor specificity of CYP induction in vitro and in vivo. The HepG2 cell line was transiently transfected with CYP2B6- and CYP3A4-luciferase promoter reporter plasmids along with human PXR (hPXR) or hCAR expression vectors. In the presence of hPXR, endosulfan-alpha exposure caused significant induction of CYP2B6 (16-fold) and CYP3A4 (11-fold) promoter activities over control at 10 µM. The metabolite endosulfan sulfate also induced CYP2B6 (12-fold) and CYP3A4 (6-fold) promoter activities over control at 10 µM. In the presence of hCAR-3, endosulfan-alpha induced CYP2B6 (2-fold) promoter activity at 10 µM, but not at lower concentrations. These data indicate that endosulfan-alpha significantly activates hPXR strongly and hCAR weakly. Using western blot analysis of human hepatocytes, the lowest concentrations at which CYP2B6 and CYP3A4 protein levels were found to be significantly elevated by endosulfan-alpha were 1.0 µM and 10 µM, respectively. In mPXR-null/hPXR-transgenic mice, endosulfan-alpha exposure (2.5 mg/kg/day) caused a significant reduction of tribromoethanol-induced sleep times by approximately 50%, whereas no significant change in sleep times was observed in PXR-null mice. These data support the role of endosulfan-alpha as a strong activator of PXR and inducer of CYP2B6 and CYP3A4, which may impact metabolism of CYP2B6 or CYP3A4 substrates.     

CYP2C9、CYP2C19、CYP3A4基因多态性对磺脲类降糖药代谢的影响

磺脲类口服降糖药在人体内主要经过肝脏代谢。肝脏中的细胞色素氧化酶P450是一种重要的药物代谢酶系统,在人群中存在基因多态性,导致药物疗效和不良反应在个体间存在着较大的差异。本文将对CYP450中的几种重要的代谢酶亚型CYP2C9、CYP2C19、CYP3A4的基本结构、基因多态性、种族差异及其对磺脲类降糖药代谢的影响作一综述。     

Pharmacokinetics of midazolam in CYP3A4- and CYP3A5-genotyped subjects

Objective We investigated whether differences in pharmacokinetics of midazolam, a CYP3A probe, could be demonstrated between subjects with different CYP3A4 and CYP3A5 genotypes.Methods Plasma concentrations of midazolam, and of total (conjugated + unconjugated) 1OH-midazolam, and 4OH-midazolam were measured after the oral administration of 7.5 mg or of 75 µg of midazolam in 21 healthy subjects.Results CYP3A5*7, CYP3A4*1E, CYP3A4*2, CYP3A4*4, CYP3A4*5, CYP3A4*6, CYP3A4*8, CYP3A4*11, CYP3A4*12, CYP3A4*13, CYP3A4*17 and CYP3A4*18 alleles were not identified in the 21 subjects. CYP3A5*3, CYP3A5*6, CYP3A4*1B and CYP3A4*1F alleles were identified in 20, 1, 4 and 2 subjects, respectively. No statistically significant differences were observed for the AUC_inf values between the different genotypes after the 75-µg or the 7.5-mg dose.Conclusion Presently, CYP3A4 and CYP3A5 genotyping methods do not sufficiently reflect the inter-individual variability of CYP3A activity.     

PXR受体调控的CYP3A诱导及其在药物代谢中的重要意义

机体每日都要接触大量外源性化合物（xenobiotics），包括环境、饮食、药物中的各种成分，其中亲脂性化合物如果不能被及时代谢为极性化合物，就会在肝脏蓄积并影响机体正常生理功能，产生毒性甚至致癌。细胞色素P450（CYPS）属于血红素蛋白基因超家族，编码一系列代谢酶系统，参与各类不同结构亲脂性化合物的生物转化，增强代谢物水溶性，利于排出体外，