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1.
Xenobiotica ; 34(6): 549-69, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15277015

ABSTRACT

1. The results of homology modelling of cytochrome P4503A4 (CYP3A4), which is a human enzyme of major importance for the Phase 1 metabolism of drug substrates, from the CYP2C5 crystal structure is reported. 2. The overall homology between the two protein sequences was generally good (46%) with 24% of amino acid residues being identical and a 22% similarity between matched pairs in the CYP3A4 and CYP2C5 aligned sequences, thus indicating that CYP2C5 represents a viable template for modelling CYP3A4 by homology. 3. The CYP3A4 model appears to show consistency with the reported findings from the extensive site-directed mutagenesis studies already published. 4. Typical CYP3A4 substrates, such as midazolam, testosterone, nifedipine and verapamil, are shown to fit the putative active site of the enzyme structure in a manner consistent with their known positions of metabolism.


Subject(s)
Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/metabolism , Models, Molecular , Steroid 21-Hydroxylase/chemistry , Amino Acid Sequence , Binding Sites , Crystallography, X-Ray , Cytochrome P-450 CYP3A , Cytochrome P450 Family 2 , Humans , Molecular Sequence Data , Molecular Structure , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/metabolism , Sequence Alignment , Sequence Homology, Amino Acid , Substrate Specificity
2.
Xenobiotica ; 33(3): 239-54, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12637242

ABSTRACT

1. The results of homology modelling of human cytochrome P4501A2 (CYP1A2) based on the CYP2C5 crystal structure are reported. It exhibits improved sequence homology relative to that of CYP102. 2. It was demonstrated that many selective substrates for CYP1A2 could fit within the putative active site of the enzyme, and in orientations which agree with documented evidence for CYP1A2-mediated metabolism. 3. Furthermore, a number of amino acid residues lining the haem pocket have been shown, via site-directed mutagenesis, to have an influence on substrate metabolism, and these experimental findings from the literature are consistent with the modelled interactions for selective substrates. 4. The binding affinities of several CYP1A2 substrates have also been calculated from the CYP1A2 active site interactions and they agree closely with experimental values.


Subject(s)
Cytochrome P-450 CYP1A2/chemistry , Cytochrome P-450 Enzyme System/chemistry , Steroid 21-Hydroxylase/chemistry , Amino Acid Sequence , Animals , Chemical Phenomena , Chemistry, Physical , Cricetinae , Crystallography, X-Ray , Cytochrome P450 Family 2 , Fishes , Humans , Lipids/chemistry , Mice , Models, Molecular , Molecular Sequence Data , Mutagenesis, Site-Directed , Rabbits , Species Specificity
3.
Toxicol In Vitro ; 17(2): 179-90, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12650672

ABSTRACT

The results of homology modelling of the human P450 enzyme CYP2A6, based on the CYP2C5 crystallographic template structure are reported. A substantial number of selective substrates of the CYP2A6 enzyme fit the putative active site in a manner that is consistent with their known metabolites. Moreover, the evidence from site-directed mutagenesis experiments is in accordance with the current model, particularly in relation to complementary amino acid contacts within the haem environment. The binding of substrates is rationalized in terms of QSAR analyses and from a consideration of the contributory factors affecting the binding affinity. The latter approach appears to represent a highly correlated (R=0.99) method for estimating the relative strength of enzyme-substrate binding within CYP2A6-selective compounds, albeit within a fairly limited dataset of substrates.


Subject(s)
Aryl Hydrocarbon Hydroxylases/chemistry , Cytochrome P-450 Enzyme System/chemistry , Mixed Function Oxygenases/chemistry , Quantitative Structure-Activity Relationship , Steroid 21-Hydroxylase/chemistry , Amino Acid Sequence , Aryl Hydrocarbon Hydroxylases/genetics , Binding Sites , Crystallography , Cytochrome P-450 CYP2A6 , Cytochrome P-450 Enzyme System/genetics , Cytochrome P450 Family 2 , Humans , Kinetics , Mixed Function Oxygenases/genetics , Models, Molecular , Molecular Sequence Data , Mutagenesis, Site-Directed , Sequence Alignment , Sequence Homology , Steroid 21-Hydroxylase/genetics , Substrate Specificity , Templates, Genetic
4.
Toxicol In Vitro ; 17(1): 93-105, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12537967

ABSTRACT

The construction of a homology model of human cytochrome P450 2E1 (CYP2E1) is reported, based on the CYP2C5 crystallographic template. A relatively high degree of primary sequence homology (identity=59%), as expected for proteins of the same CYP family, ensured a straightforward generation of the 3-dimensional model due to relatively few deletions and insertions of amino acid residues with respect to the CYP2C5 crystal structure. Probing the CYP2E1 model with typical substrates of the enzyme showed a good agreement with experimental information in the form of positions of metabolism for substrates, and with site-directed mutagenesis data on certain residues. Furthermore, quantitative relationships between substrate binding affinity and various structural parameters associated with the substrate molecules facilitated the formulation of a procedure for estimating relative binding energy and, consequently, K(m) or K(D) values towards the CYP2E1 enzyme. This method has been based on a consideration of the active site interactions between substrates and key amino acid residues lining the haem pocket, together with compound lipophilicity data from partition coefficients.


Subject(s)
Cytochrome P-450 CYP2E1/pharmacology , Models, Molecular , Sequence Alignment , Amino Acid Sequence , Crystallization , Humans , Molecular Sequence Data
5.
J Steroid Biochem Mol Biol ; 82(2-3): 195-9, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12477485

ABSTRACT

The results of homology modelling of the human glucorticoid receptor (hGR) ligand-binding domain (LBD) based on the ligand-bound domain of the human estrogen receptor alpha (hERalpha) are reported. It is shown that known hGR ligands which induce the human cytochrome P450 enzyme CYP3A4 are able to fit the putative ligand-binding site of the nuclear hormone receptor and form hydrogen bonds with key amino acid residues within the binding pocket. Quantitative structure-activity relationships (QSARs) have been derived for hGR-mediated CYP3A4 induction which involve certain molecular structural and physicochemical properties of the ligand themselves, yielding good correlations (R=0.96-0.98) with fold induction of CYP3A4 known to be mediated via hGR involvement.


Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Protein Structure, Tertiary , Receptors, Estrogen/chemistry , Receptors, Glucocorticoid/chemistry , Receptors, Glucocorticoid/metabolism , Amino Acid Sequence , Binding Sites , Cytochrome P-450 CYP3A , Enzyme Induction , Estrogen Receptor alpha , Humans , Hydrogen Bonding , Ligands , Models, Molecular , Molecular Sequence Data , Quantitative Structure-Activity Relationship , Receptors, Estrogen/genetics , Receptors, Estrogen/metabolism , Receptors, Glucocorticoid/genetics , Sequence Alignment , Statistics as Topic
7.
Xenobiotica ; 31(6): 321-43, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11513246

ABSTRACT

1. The ability of various in vitro systems for CYP enzymes (computer modelling, human liver microsomes, precision-cut liver slices, hepatocytes in culture, recombinant enzymes) to predict various aspects of in vivo metabolism and kinetics of carbamazepine (CBZ) was investigated. 2. The study was part of the EUROCYP project that aimed to evaluate relevant human in vitro systems to study drug metabolism. 3. CBZ was given to the participating laboratories without disclosing its chemical nature. 4. The most important enzyme (CYP3A4) and metabolic route (10,11-epoxidation) were predicted by all the systems studied. 5. Minor enzymes and routes were predicted to a different extent by various systems. 6. Prediction of a clearance class, i.e. slow clearance, was correctly predicted by microsomes, slices, hepatocytes and recombinant enzymes (CYP3A4). 7. The 10,11-epoxidation of CBZ by the recombinant CYP3A4 was enhanced by the addition of exogenous cytochrome-b5, leading to a considerable over-prediction. 8. Induction potency of CBZ was predicted in cultured hepatocytes in which 7-ethoxycoumarin O-deethylase was used as an index activity. 9. It seems that for a principally CYP-metabolized substance such as CBZ, all liver-derived systems provide useful information for prediction of metabolic routes, rates and interactions.


Subject(s)
Anticonvulsants/metabolism , Carbamazepine/metabolism , Cytochrome P-450 Enzyme System/metabolism , Liver/enzymology , Cells, Cultured , Computer Simulation , Cytochrome P-450 CYP3A , Epoxy Compounds/metabolism , Hepatocytes/metabolism , Humans , In Vitro Techniques , Kinetics , Microsomes, Liver/enzymology , Mixed Function Oxygenases/metabolism , Recombinant Proteins/metabolism
9.
Drug Metab Dispos ; 29(5): 712-20, 2001 May.
Article in English | MEDLINE | ID: mdl-11302938

ABSTRACT

The ability of various human derived in vitro systems to predict various aspects of the in vivo metabolism and kinetics of almokalant have been investigated in a multicenter collaborative study. Although almokalant has been withdrawn from further clinical development, its metabolic and pharmacokinetic properties have been well characterized. Studies with precision-cut liver slices, primary hepatocyte cultures, and hepatic microsomal fractions fortified with UDP-glucuronic acid all suggested that almokalant is mainly glucuronidated to the stereoisomers M18a and M18b, which is in good agreement with the results in vivo. Both in vivo and in vitro studies indicate that the formation of M18b dominates over that of M18a, although the difference is more pronounced with the in vitro systems. Molecular modeling, cDNA-expressed enzyme analysis, correlation analysis, and inhibition studies did not clearly indicate which P450 enzymes catalyze the oxidative pathways, which may indicate a problem in identifying responsible enzymes for minor metabolic routes by in vitro methods. All of the in vitro systems underpredicted the metabolic clearance of almokalant, which has previously been reported to be a general problem for drugs that are cleared by P450-dependent metabolism. Although few studies on in vivo prediction of primarily glucuronidated drugs have appeared, in vitro models may consistently underpredict in vivo metabolic clearance. We conclude that in vitro systems, which monitor phase II metabolism, would be beneficial for prediction of the in vivo metabolism, although all of the candidate liver-derived systems studied here, within their intrinsic limitations, provided useful information for predicting metabolic routes and rates.


Subject(s)
Anti-Arrhythmia Agents/metabolism , Microsomes, Liver/metabolism , Propanolamines/metabolism , Anti-Arrhythmia Agents/pharmacokinetics , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Hepatocytes/metabolism , Humans , In Vitro Techniques , Microsomes, Liver/enzymology , Propanolamines/pharmacokinetics
11.
Xenobiotica ; 30(1): 1-25, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10659948

ABSTRACT

1. The construction of a three-dimensional model of human CYP2E1 is reported. It is based on homology with the haemoprotein domain of the unusual bacterial P450, CYP102, which is of known crystal structure. 2. Interactive docking of a number of human CYP2E1 substrates is consistent with their known positions of CYP2E1-mediated metabolism, where specific interactions with key active site amino acid side-chains appear to rationalize the binding and orientation of substrate molecules. 3. Amino acid residues within the putative active site of human CYP2E1, including those associated with the binding of substrates and inhibitors, are shown to correspond with those identified by site-directed mutagenesis experiments conducted on CYP2 family isoforms, and they are known to affect substrate metabolism regioselectivity. 4. Consequently, it was found that the CYP2E1 active site exhibits complementarity with the structural characteristics of known substrates and inhibitors of this enzyme, including their relatively low molecular weights and disposition of hydrogen bond-forming groups.


Subject(s)
Bacterial Proteins , Cytochrome P-450 CYP2E1/chemistry , Cytochrome P-450 Enzyme System/chemistry , Mixed Function Oxygenases/chemistry , Amino Acid Sequence , Binding Sites , Crystallography, X-Ray , Cytochrome P-450 CYP2E1/metabolism , Cytochrome P-450 CYP2E1 Inhibitors , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Isoenzymes/chemistry , Mixed Function Oxygenases/antagonists & inhibitors , Mixed Function Oxygenases/metabolism , Models, Molecular , Models, Structural , Molecular Sequence Data , NADPH-Ferrihemoprotein Reductase , Sequence Homology, Amino Acid , Structure-Activity Relationship , Substrate Specificity , Templates, Genetic
13.
Toxicology ; 139(1-2): 53-79, 1999 Nov 29.
Article in English | MEDLINE | ID: mdl-10614688

ABSTRACT

Molecular modelling of a number of CYP1 family enzymes from rat, plaice and human is described based on amino acid sequence homology with the haemoprotein domain of CYP102, a unique bacterial P450 of known structure. The interaction of various substrates and inhibitors within the putative active sites of rat CYP1A1, human CYP1A2, a fish CYP1 enzyme CYP1A6 (from plaice) and human CYP1B1, is shown to be consistent with P450-mediated oxidation in each example or, in the case of inhibitors, mechanism of inhibition. It is reported that relatively small changes between the enzymes' active site regions assist in the rationalization of CYP1 enzyme preferences for particular substrate types, and a template of superimposed CYP1A2 substrates is shown to fit the putative active site of the human CYP1A2 enzyme.


Subject(s)
Aryl Hydrocarbon Hydroxylases , Bacterial Proteins , Cytochrome P-450 CYP1A1/chemistry , Cytochrome P-450 CYP1A2/chemistry , Cytochrome P-450 Enzyme System/chemistry , Mixed Function Oxygenases/chemistry , Xenobiotics/metabolism , Animals , Cricetinae , Cytochrome P-450 CYP1A1/antagonists & inhibitors , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP1A2/genetics , Cytochrome P-450 CYP1A2 Inhibitors , Cytochrome P-450 CYP1B1 , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/genetics , Enzyme Inhibitors/pharmacology , Flatfishes , Humans , Hydrogen Bonding , Mice , Mixed Function Oxygenases/antagonists & inhibitors , Mixed Function Oxygenases/genetics , Models, Molecular , Mutagenesis, Site-Directed , NADPH-Ferrihemoprotein Reductase , Oxidation-Reduction , Rabbits , Rats , Sequence Homology, Amino Acid , Species Specificity , Structure-Activity Relationship
14.
Toxicology ; 133(1): 1-33, 1999 Mar 01.
Article in English | MEDLINE | ID: mdl-10413191

ABSTRACT

(1) The generation of a homology model of CYP2A6, the major catalyst of human hepatic coumarin 7-hydroxylase activity, involves the use of the recently published substrate-bound CYP102 crystal structure as a template. (2) A substantial number of structurally diverse CYP2A6 substrates are found to dock satisfactorily within the putative active site of the enzyme, leading to the formulation of a structural template (or pharmacophore) for CYP2A6 specificity/selectivity. (3) The CYP2A6 model is consistent with available evidence from site-directed mutagenesis studies carried out on CYP2A subfamily isoforms, and enables some explanation of species differences in CYP2A-mediated metabolism of certain substrates. (4) Quantitative structure-activity relationship (QSAR) analysis of CYP2A5 (the mouse orthologue) mutants yields statistically significant correlations between various properties of amino acid residues and coumarin 7-hydroxylase activity.


Subject(s)
Aryl Hydrocarbon Hydroxylases , Cytochrome P-450 Enzyme System/chemistry , Mixed Function Oxygenases/chemistry , Models, Molecular , Amino Acid Sequence , Animals , Coumarins/metabolism , Cytochrome P-450 CYP2A6 , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/genetics , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P450 Family 2 , Fadrozole/metabolism , Furans/metabolism , Humans , Mice , Mixed Function Oxygenases/antagonists & inhibitors , Mixed Function Oxygenases/genetics , Mixed Function Oxygenases/metabolism , Molecular Sequence Data , Structure-Activity Relationship , Substrate Specificity
15.
Xenobiotica ; 29(4): 361-93, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10375007

ABSTRACT

1. Molecular modelling studies of CYP2B isoforms from rat (CYP2B1), rabbit (CYP2B4) and man (CYP2B6) are reported, with particular emphasis on substrate interactions with the human CYP2B isoform, CYP2B6. 2. The findings represent an advance on our previous study that focused primarily on the rat CYP2B isoform, CYP2B1, and involved homology modelling with substrate-free CYP102. 3. The current work utilizes the recently published substrate-bound CYP102 crystal structure as a template for construction of the CYP2B subfamily isoforms and shows, in particular, that known CYP2B6 substrate specificity and regioselectivity can be rationalized by putative active site interactions.


Subject(s)
Aryl Hydrocarbon Hydroxylases , Bacterial Proteins , Crystallography, X-Ray , Cytochrome P-450 CYP2B1/chemistry , Cytochrome P-450 Enzyme System/chemistry , L-Lactate Dehydrogenase/chemistry , Mixed Function Oxygenases/chemistry , Models, Molecular , Oxidoreductases, N-Demethylating/chemistry , Steroid Hydroxylases/chemistry , Amino Acid Sequence , Animals , Binding Sites , Cytochrome P-450 CYP2B6 , Humans , Hydrogen-Ion Concentration , Kinetics , L-Lactate Dehydrogenase (Cytochrome) , Molecular Sequence Data , Mutagenesis, Site-Directed , NADPH-Ferrihemoprotein Reductase , Rabbits , Rats , Sequence Homology, Amino Acid , Structure-Activity Relationship , Substrate Specificity
16.
Xenobiotica ; 29(3): 269-79, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10219967

ABSTRACT

1. A plasmid containing 1 kb of the CYP3A4 regulatory (promoter) region coupled to a reporter gene for secretary placental alkaline phosphatase (SPAP) was transfected into HepG2 cells. Transfected cells were dosed with several known inducers of CYP3A4 and the levels of SPAP were measured. The effect of co-transfecting a plasmid encoding the human glucocorticoid receptor on reporter gene activity was also examined. 2. Dexamethasone induced CYP3A4-dependent reporter gene expression in a concentration-dependent manner and induction was approximately doubled in the presence of the glucocorticoid receptor. Dexamethasone-dependent induction was blocked by RU-486 (a glucocorticoid receptor antagonist), in the presence of the co-transfected glucocorticoid receptor. 3. Induction of CYP3A4-dependent reporter gene expression and enhancement of the induction by the glucocorticoid receptor was also observed with pregnenolone-16alpha-carbonitrile (PCN), rifampicin, phenytoin, carbamazepine, phenylbutazone and phenobarbitone, all known in vivo inducers of CYP3A4 in man. 4. Metyrapone and sulfinpyrazone induced CYP3A4-dependent reporter gene expression, but induction was not enhanced by the glucocorticoid receptor. 5. Clotrimazole, erythromycin and triacetyloleandomycin (TAO) did not induce CYP3A4-dependent reporter gene expression, consistent with the observation that these inducers act through post-transcriptional mechanisms. 6. These results highlight differences in the molecular mechanisms of induction of CYP3A4 by the xenobiotics studied and indicate that the glucocorticoid receptor is involved in the induction of the CYP3A4 gene by some, but not all, CYP3A4 inducers. 7. We propose that the approach described here provides a useful in vitro approach for the identification of transcriptional regulators of the CYP3A4 gene.


Subject(s)
Cytochrome P-450 Enzyme System/drug effects , Cytochrome P-450 Enzyme System/genetics , Drug Evaluation, Preclinical/methods , Mixed Function Oxygenases/drug effects , Mixed Function Oxygenases/genetics , Xenobiotics/pharmacology , Alkaline Phosphatase/genetics , Caffeine/pharmacology , Carbamazepine/pharmacology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Clofibrate/pharmacology , Cytochrome P-450 CYP3A , Dexamethasone/pharmacology , Dose-Response Relationship, Drug , Gene Expression Regulation/drug effects , Genes, Reporter , Glucocorticoids/pharmacology , Hormone Antagonists/pharmacology , Humans , Isoniazid/pharmacology , Mifepristone/pharmacology , Phenobarbital/pharmacology , Phenylbutazone/pharmacology , Phenytoin/pharmacology , Receptors, Glucocorticoid/drug effects , Receptors, Glucocorticoid/genetics , Recombinant Proteins/drug effects , Recombinant Proteins/genetics , Rifampin/pharmacology , Tumor Cells, Cultured/drug effects , beta-Naphthoflavone/pharmacology
18.
Drug Metabol Drug Interact ; 15(1): 1-49, 1999.
Article in English | MEDLINE | ID: mdl-10707112

ABSTRACT

The structural characteristics of human cytochrome P450 substrates are outlined in the light of extensive studies on P450 substrate specificity. Templates of superimposed substrates for individual P450 isozymes are shown to fit the corresponding enzyme active sites, where contacts with specific amino acid residues appear to be involved in the interaction with each structural template. Procedures leading to the evaluation of likely P450 specificity, binding affinity and rate of metabolism are described in the context of key examples in which molecular modelling appears to rationalize experimentally observed findings.


Subject(s)
Cytochrome P-450 CYP1A2 , Cytochrome P-450 CYP2D6 , Cytochrome P-450 CYP2E1 , Cytochrome P-450 Enzyme System , Animals , Binding Sites , Cytochrome P-450 CYP1A2/chemistry , Cytochrome P-450 CYP1A2/metabolism , Cytochrome P-450 CYP2D6/chemistry , Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 CYP2E1/chemistry , Cytochrome P-450 CYP2E1/metabolism , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/metabolism , Humans , Mice , Molecular Structure , Rabbits , Rats , Substrate Specificity
19.
Chem Biol Interact ; 115(3): 175-99, 1998 Oct 02.
Article in English | MEDLINE | ID: mdl-9851289

ABSTRACT

The structural characteristics of cytochrome P450 substrates are summarised, showing that molecular descriptors can discriminate between chemicals of differing P450 isozyme specificity. Procedures for the estimation of P450 substrate binding interaction energies and rates of metabolism are described, providing specific examples in both individual compounds binding to P450s, including those of known crystal structure, and within series of structurally related chemicals. It is demonstrated that binding energy components are primarily hydrophobic/desolvation and electrostatic/hydrogen-bonded in nature, whereas electronic factors are of importance in determining variations in reaction rates. It is thus shown that the prediction of P450 substrate binding affinities and catalytic rates may be feasible, provided that sufficient structural information is available for the relevant enzyme-substrate complex.


Subject(s)
Cytochrome P-450 Enzyme System/chemistry , Animals , Binding Sites , Catalysis , Cytochrome P-450 Enzyme System/metabolism , Humans , Isoenzymes/chemistry , Isoenzymes/metabolism , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Substrate Specificity
20.
Xenobiotica ; 28(3): 235-68, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9574814

ABSTRACT

1. The results of molecular modelling of human CYP2C isozymes, CYP2C9 and CYP2C19, are reported based on an alignment with a bacterial form of the enzyme, CYP102. 2. The three-dimensional structures of the CYP2C enzymes are consistent with known experimental evidence from site-directed mutagenesis, antibody recognition and regiospecificity of substrate metabolism. 3. The variations in substrate specificity between CYP2C9 and CYP2C19 can be rationalized in terms of single amino acid residue changes within the putative active site region, of which I99H appears to be the most significant.


Subject(s)
Aryl Hydrocarbon Hydroxylases , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/genetics , Isoenzymes/chemistry , Isoenzymes/genetics , Mixed Function Oxygenases/chemistry , Mixed Function Oxygenases/genetics , Models, Molecular , Steroid 16-alpha-Hydroxylase , Steroid Hydroxylases/chemistry , Steroid Hydroxylases/genetics , Amino Acid Sequence , Cytochrome P-450 CYP2C19 , Cytochrome P-450 CYP2C9 , Cytochrome P-450 Enzyme System/metabolism , Humans , Isoenzymes/metabolism , Mixed Function Oxygenases/metabolism , Molecular Sequence Data , Mutagenesis, Site-Directed , Sequence Alignment , Species Specificity , Steroid Hydroxylases/metabolism , Substrate Specificity
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