Cytochrome P450 3A7 Oxygen Cytochrome P450 26 CYP2R1 pyrophosphate Cytochrome P450 2W1 H2O 4-cholesten-7alpha, 12alpha,27-triol-3- one H+ alcohol dehydrogenase complex H+ Cholesterol NADP+ Acetaldehyde NADP+ NADPH 4-Aminobiphenyl Oxygen Formate TBXAS1 Oxindole Phenylacetaldehyde Oxygen H+ H2O 24- hydroxycholesterol Oxygen H2O NADPH H+ Oxygen H+ H+ H2O 4-hydroxyestradiol- 17beta 4,4- dimethylcholesta-8 (9),14,24-trien- 3beta-ol H2O NADP+ Cytochrome P450 4F2 CYP2D6 Progesterone Phenol Cytochrome P450 4F8 Oxygen NADPH Leukotriene B4 Spermine Formaldehyde H+ H2O H+ NADPH 9-cis-retinoic acid Arachidonate Oxygen Methimazole Oxygen H2O2 NADPH NADPH Indole H+ NADPH NADPH Debrisoquine NADP+ Arachidonate H2O Coumarin Prostaglandin H2 Testosterone N-acetylspermidine Spermidine Oxidase (SMOX) CoA-SH NADPH NADP+ 5-Hydroxytryptamine Trimethylamine Cytochrome P450 26C1 CYP3A43 H2O NADP+ 3-acetamidopropanal NADP+ Hydrogen Oxygen NADPH Oxygen 4-hydroxyphenytoin NADPH 3-acetamidopropanal Vitamin D3 NADP+ H2O H+ 1,24,25- trihydroxyvitamin D3 H2O Cytochrome P450 2C19 Oxygen 24- hydroxycholesterol N-acetylspermine Dextromethorphan H2O Trichloromethyl radical NADP+ NADPH Cytochrome p450 46A1 H2O Estradiol-17beta NADP+ 19- hydroxyprostaglandin H2 3-methylindole H+ CYP11B1 NADPH 4-Androstene-3, 17- dione Oxygen H+ NADP+ 3-hydroxypalmitate NADP+ Tamoxifen N-oxide H+ ChEBI 37623 Uniprot P05108 NADP+ NADH ChEBI 16827 ChEBI 16521 2-Phenylethylamine ChEBI 42977 Cytochrome P450 7B1 ChEBI 16973 NADPH ChEBI 17026 Reactome REACT_10253 ChEBI 1294 ChEBI 17650 Oxygen Aflatoxin exo-8,9- oxide H2O Uniprot P05093 3-methyleneindolenine Estrone NADP+ 4-hydroxy-all-trans- retinoic acid H2O Oxygen ChEBI 15377 Oxygen Uniprot P98187 Cytochrome P450 3A4 Uniprot P24557 H2O ChEBI 10545 H2O H+ CYP21A2 6-hydroxypaclitaxel 19-hydroxyarachidonic acid NADP+ NADPH Spermidine ChEBI 15554 Pregnenolone H+ Uniprot Q08477 Uniprot Q16647 ChEBI 17263 ChEBI 15378 ChEBI 18009 Reactome REACT_14525 ChEBI 37248 Oxygen Reactome REACT_14617 NADP+ Uniprot Q8TAV3 Uniprot Q9UNU6 H+ H+ Uniprot P19099 ChEBI 17703 ChEBI 17998 Uniprot Q9Y6A2 ChEBI 15552 4- hydroxycyclophospham ide Ethanol ChEBI 15724 NADPH Reactome REACT_14315 NADPH ChEBI 18139 ChEBI 41774 NADP+ Reactome REACT_14663 Prostaglandin H2 Acetyl-CoA H2O2 Uniprot Q9HBI6 Cytochrome P450 2A6 H2O Oxygen Cytochrome P450 4F11 Reactome REACT_20049 17alpha- hydroxypregnenolone ChEBI 27647 ChEBI 16240 ATP NADPH ChEBI 16134 Uniprot P78329 ChEBI 16474 Reactome REACT_13855 ChEBI 15627 Cholest-5-ene-3beta, 7alpha,24(S)-triol NH3 Cytochrome P450 2C9 ChEBI 18397 NADP+ NADPH H2O ChEBI 28790 ChEBI 50157 Oxygen ChEBI 15760 Oxygen ChEBI 15621 NADP+ 20-OH-leukotriene B4 NADP+ NADPH Halothane ChEBI 30322 Prostacyclin ChEBI 17312 Oxygen Reactome REACT_14616 ChEBI 17927 ChEBI 16424 NAD+ Oxygen Reactome REACT_14612 Uniprot Q16696 Oxygen Reactome REACT_14369 CYP17A1 Uniprot P04798 Reactome REACT_14339 Cytochrome P450 39A1 ChEBI 15746 H+ ChEBI 17148 NADPH Ethylene oxide ChEBI 18090 ChEBI 16027 ChEBI 16610 Oxygen Cytochrome P450 3A5 ChEBI 4026 Oxygen Oxygen NADPH Uniprot P10632 Uniprot P24462 Reactome REACT_14465 H2O Reactome REACT_14215 H2O H2O ChEBI 15846 NADPH ChEBI 15422 6beta- hydroxytestosterone Cytochrome P450 2U1-1 ChEBI 16908 ChEBI 15346 ChEBI 15351 H+ NADPH H2O 25- hydroxycholesterol H2O NADP+ NADPH Uniprot P24903 Uniprot P20815 Uniprot P33261 ChEBI 18153 Reactome REACT_21845 Reactome REACT_14596 ChEBI 29888 Uniprot Q9NR19 H+ ChEBI 15366 H+ NADPH Oxygen Uniprot Q9NUB1 Cytochrome P450 27 CoA-SH 3,16- dihydroxypalmitate Reactome REACT_14364 Uniprot P11509 ChEBI 9171 ChEBI 27561 H+ ChEBI 29133 lanosterol NADPH ChEBI 28794 Cytochrome P450 1A1 ChEBI 15646 NADP+ ChEBI 4470 Oxygen NADP+ Trimethyamine N- oxide Methimazole S- oxide Reactome REACT_10249 ChEBI 28477 Reactome REACT_10645 Cyclophosphamide ChEBI 17899 N-demethylated loperaminde Reactome REACT_10863 Cytochrome P450 4A11 H2O Uniprot O75881 ChEBI 28750 PTGS dimers CYP51A1 ChEBI 30751 NADPH H+ Cytochrome P450 2F1 4-cholesten-7alpha, 12alpha,24(S)-triol-3- one Uniprot Q16678 Uniprot Q02318 H+ H2O Cytochrome P450 2B6 NADPH NADP+ Reactome REACT_10821 ChEBI 15843 ATP Reactome REACT_14302 H+ Uniprot P51589 H2O ChEBI 30805 PTGIS Tamoxifen Uniprot P11511 Carbon tetrachloride Uniprot Q9NYL5 ChEBI 16422 Uniprot P08686 Vinyl chloride ChEBI 28324 Reactome REACT_14354 cis-EET Uniprot Q02928 ChEBI 39567 Cytochrome P450 2J2 Reactome REACT_14303 Uniprot P13584 ChEBI 16581 ChEBI 34310 H2O Uniprot Q16850 Oxygen ChEBI 16113 Uniprot P15538 Reactome REACT_14607 Oxygen NADP+ ChEBI 17347 NAD+ 6beta- hydroxytestosterone Uniprot Q9HCS2 Ethylene Uniprot P33260 Reactome REACT_13974 Reactome REACT_14175 Thromboxane A2 ChEBI 16469 Acetaldehyde Oxygen NADPH H+ Cytochrome P450 2C8 ChEBI 37640 Tyramine ChEBI 17500 Uniprot P22680 Pregnenolone Oxygen H+ Cholest-5-ene- 3beta,7alpha,25- triol H+ H+ H2O Cytochrome P450 1B1 H+ NADP+ H+ Homo sapiens Acetaminophen (TN TYLENOL) Phase 1 of metabolism is concerned with <i><b>functionalization</b></i>, that is the introduction or exposure of functional groups on the chemical structure of a compound. This provides a 'handle' for phase 2 conjugating species with which to react with. Many xenobiotics are lipophilic and almost chemically inert (e.g. PAHs) so would not necessarily undergo a phase 2 reaction. Making them more chemically reactive would facilitate their excretion but also increases their chance of reacting with cellular macromolecules (e.g. proteins, DNA). There is a fine balance between producing a more reactive metabolite and conjugation reactions.<br>There are two groups of enzymes in phase 1 - oxidoreductases and hydrolases. Oxidoreductases introduce an oxygen atom into or remove electrons from their substrates. The major oxidoreductase enzyme system is called the P450 monooxygenases. Other systems include flavin-containing monooxygenases (FMO), cyclooxygenases (COX) and monoamine oxidases (MAO). Hydrolases hydrolyse esters, amides, epoxides and glucuronides. (WikiPathways-description) Cellular Process (WikiPathways-category) Phase 1 - Functionalization of compounds Reactome REACT_14313 ChEBI 15379 ChEBI 15647 H2O H2O H+ H+ NADP+ NADPH Oxygen H+ Cytochrome P450 8B1 H2O H+ ChEBI 6532 H+ H2O NADP+ Uniprot P10635 CYP2S1 Reactome REACT_14274 ChEBI 2504 Reactome REACT_13828 NADPH 1,25-dihydroxyvitamin D3 H2O H2O2 NADP+ Hydrogen bromide Oxygen NADP+ 12-hydroxy- 5,8,11,14- eicosatetraenoic acid NADPH Ethanol NADP+ Oxygen Isocaproic aldehyde Cytochrome P450 7A1 H+ Calcidiol NADPH H+ Corticosterone Oxygen Cytochrome P450 2E1 NADPH NADP+ H2O H2O 11- deoxycorticosterone Oxygen NADPH Putrescine NADP+ Acetate Oxygen NADPH Tolbutamide NADPH NADH NADP+ Acetate Hydroxycoumarin Oxygen 4-cholesten-7alpha, 24(S)-diol-3-one Oxygen CYPIA2 H2O ACSS1 All-trans-retinoic acid H+ H+ Oxygen Aflatoxin B1 Testosterone NADPH Oxygen H+ 11- deoxycorticosterone NADPH NADP+ NADPH Oxygen H2O H2O Cholesterol Oxygen Oxygen H2O NADP+ H+ Oxygen Chloride 5- Hydroxyindoleacetalde hyde NADP+ Oxygen NADPH NADP+ NADPH Phenytoin NADP+ NADH NADPH NADPH H2O Oxygen Calcitriol NADP+ 4-hydroxytolbutamide Oxygen H2O NADP+ AMP H2O Prostaglandin G2 H2O H+ N-Hydroxy-4- aminobiphenyl H+ 11-deoxycortisol Acetyl-CoA electron Oxygen omega- Hydroxydodecanoic acid NADPH 4-hydroxy-9-cis- retinoic acid Cytochrome P450 4F12 H2O2 4-hydroxydebrisoquine H2O2 CYP11A1 Dodecylcarboxylate NADPH NADP+ NADP+ H2O CYP19A1 Oxygen Benzene NH3 Cytochrome P450 4F3 H2O Oxygen Uniprot P20813 Acetyl-coenzyme A synthetase, cytoplasmic Oxygen H2O ChEBI 25858 ChEBI 16842 Reactome REACT_14384 ChEBI 2505 Oxygen H+ H+ H2O Oxygen H2O2 4- Hydroxyphenylacetalde hyde H2O ChEBI 27732 Oxygen ChEBI 16580 H2O ChEBI 5615 Uniprot P05177 ChEBI 1784 H2O Oxygen H+ H2O H+ NADP+ Formate Oxygen Loperamide Paclitaxel Uniprot P11712 The start coordinate is not yet known (WikiPathways-description) CYP27B1 Reactome REACT_14076 NADPH Uniprot P08684 ChEBI 45863 ChEBI 27510 H2O Cortisol Formaldehyde Cytochrome P450 4B1 NADPH H2O H2O NADPH NADP+ H2O 7 alpha- hydroxycholesterol Uniprot P05181 ChEBI 29132 ChEBI 16236 ChEBI 15882 ChEBI 16716 3-aminopropanal H2O NADPH H2O Spermidine Reactome REACT_14412 H2O Uniprot Q6VVX0 Reactome REACT_14555 ChEBI 28940 Reactome REACT_14066 Oxygen NAD+ H2O Acetaldehyde H+ ChEBI 29138 ChEBI 15343 Cytochrome P450 26B1 ChEBI 27385 Cytochrome P450 2C18 Paraxanthine ChEBI 46195 H2O ChEBI 29129 NADP+ Cytochrome P450 2A13 H+ ChEBI 28509 NADP+ ChEBI 47266 H+ Arachidonate ChEBI 17996 H+ Reactome REACT_4348 ChEBI 18276 H+ Reactome REACT_13891 NADP+ ChEBI 31697 NADP+ ChEBI 16881 CYP11B2 Uniprot Q7Z449-1 Reactome REACT_14524 H+ NADP+ PubMed J Biol Chem 275:26458-66 Hannah, VC Luong, A Goldstein, JL 2000 10843999 Molecular characterization of human acetyl-CoA synthetase, an enzyme regulated by sterol regulatory element-binding proteins. Oxygen AMP 4-cholesten-7alpha, 27-diol-3-one pyrophosphate Oxygen 4-cholesten-7alpha- ol-3-one 27- hydroxycholesterol H2O H2O CYP24A1 NADP+ 5-hydroxyomeprazole N- Acetylbenzoquinoneim ine Omeprazole NADP+ 2-Chloroethylene oxide H+ H2O NADPH ChEBI 17823 NH3 Cholesterol Uniprot Q07973 Reactome REACT_13921 NADP+ Uniprot O15528 Reactome REACT_14157 Caffeine 4-cholesten-7alpha, 12alpha-diol-3-one H+ NADP+ NADPH 18- hydroxyarachidonate Uniprot Q6V0L0 Oxygen ChEBI 15367 Reactome REACT_14163 Trifluoroacetylchloride NADPH Uniprot Q9NR63 Dextrorphan Uniprot O43174 20alpha,22beta dihydroxycholesterol