The DOI matches its Crossref record.
N4-hydroxylation of sulfamethoxazole by cytochrome P450 of the cytochrome P4502C subfamily and reduction of sulfamethoxazole hydroxylamine in human and rat hepatic microsomes
Abstract
The N4-hydroxylation of sulfamethoxazole (SMX) to its hydroxylamine (SMX-HA) metabolite is the first step in the formation of reactive metabolites responsible for mediating hypersensitivity reactions associated with this compound. In rat hepatic microsomes, the NADPH-dependent oxidation of SMX to SMX-HA was increased 3-fold by pretreatment of rats with phenobarbital. Other cytochrome P450 (CYP) inducers were ineffective. The constitutive and induced SMX N-hydroxylation activities were inhibited by tolbutamide, and induction of SMX-HA activity paralleled the induction of progesterone 21-hydroxylase activity, a marker for CYP2C6. SMX N-hydroxylation in phenobarbital-treated rat hepatic microsomes was inhibited 70% by anti-CYP2C6 antisera. Thus, the N4-hydroxylation of SMX by rat hepatic microsomes was mediated by members of the CYP2C subfamily, probably CYP2C6. In a panel of human microsomes, SMX-HA formation correlated with tolbutamide hydroxylase activity (r = 0.75; p = 0.01); CYP2C9 content (r = 0.79; p < 0.01) and was inhibited 70% by 500 microM tolbutamide and 90% by 100 microM sulfaphenazole. Recombinant CYP2C9 catalyzed the N-hydroxylation of SMX. SMX-HA formation in human hepatic microsomes was therefore mediated predominantly by CYP2C9. CYP-mediated reduction of SMX-HA to SMX was markedly induced in dexamethasone and phenobarbital-treated rat hepatic microsomes, and was attributed to CYP3A and CYP2B forms. In uninduced rat and human hepatic microsomes, SMX-HA reduction was mediated predominantly by an NADH-dependent microsomal hydroxylamine reductase under aerobic conditions. Under anaerobic conditions, troleandomycin at > or = 1 microM inhibited the reduction of SMX-HA in human hepatic microsomes by 45%, whereas sulfaphenazole had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Citations
Cites
Still being checked.
Cited by
Sorted by citations
Items 101–169 of 169
Oxygen-insensitive enzymatic reduction of oximes to imines
Heberling, S., Girreser, U., Wolf, S., & Clement, B. (2005) · Biochemical Pharmacology · doi:10.1016/j.bcp.2005.10.037 · Cited by 18
Are drug metabolites able to cause T-cell-mediated hypersensitivity reactions?
Sullivan, A. K., Gibson, A., Park, B. K., & Naisbitt, D. J. (2014) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2015.992780 · Cited by 19
Muta, K., Fukami, T., & Nakajima, M. (2015) · Biochemical Pharmacology · doi:10.1016/j.bcp.2015.09.016 · Cited by 17
Alsaad, N., Dijkstra, J. A., Akkerman, O. W., de Lange, W. C. M., van Soolingen, D., Kosterink, J. G. W., van der Werf, T. S., & Alffenaar, J. C. (2016) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02175-15 · Cited by 17
Sameer, A.-E. I., Amany, G. M., Abdela, A. A., & Fadel, S. A. (2009) · PubMed · Cited by 14
Clement, B., Behrens, D., Amschler, J., Matschke, K., Wolf, S., & Havemeyer, A. (2005) · Life Sciences · doi:10.1016/j.lfs.2004.12.028 · Cited by 14
Hess, D. A., O'Leary, E. F., Lee, J. T., Almawi, W. Y., Madrenas, J., & Rieder, M. J. (2001) · The FASEB Journal · doi:10.1096/fj.00-0583fje · Cited by 14
Depression of phenytoin metabolic capacity by 5-fluorouracil and doxifluridine in rats
Konishi, H., Yoshimoto, T., Morita, K., Minouchi, T., Sato, T., & Yamaji, A. (2003) · Journal of Pharmacy and Pharmacology · doi:10.1211/002235702298 · Cited by 14
Identification of rat cytochrome P450 forms involved in the metabolism of clausenamide enantiomers
Zhu, C. J., & Zhang, J. T. (2003) · Chirality · doi:10.1002/chir.10228 · Cited by 14
Miura, M., Takahashi, N., Kanno, S., Kato, S., Nara, M., Itoh, M., Saitoh, H., Yoshioka, T., Kameoka, Y., Fujishima, N., et al. (2011) · Clinica Chimica Acta · doi:10.1016/j.cca.2011.06.035 · Cited by 13
Wang, H., Nakajima, T., Ito, Y., Naito, H., Zhao, N., Li, H., Qiu, X., Xia, L., Chen, J., Wu, Q., et al. (2020) · Environmental Research · doi:10.1016/j.envres.2020.109972 · Cited by 13
Lv, R., Shi, R., Wu, E., Ma, C., Guo, R., Li, J., Ouyang, F., Fang, Q., Hu, L., Sun, C., et al. (2020) · Talanta · doi:10.1016/j.talanta.2020.121371 · Cited by 11
Lavergne, S. N., Volkman, E. M., Maki, J. E., Yoder, A. R., & Trepanier, L. A. (2004) · Toxicology · doi:10.1016/j.tox.2004.11.009 · Cited by 12
Yong, C., Devine, S. M., Gao, X., Yan, A., Callaghan, R., Capuano, B., & Scammells, P. J. (2019) · ChemMedChem · doi:10.1002/cmdc.201900477 · Cited by 12
Funk‐Keenan, J., Sacco, J., Wong, Y. Y., Rasmussen, S., Motsinger‐Reif, A. A., & Trepanier, L. A. (2012) · Journal of Veterinary Internal Medicine · doi:10.1111/j.1939-1676.2012.00965.x · Cited by 12
ROLE OF HUMAN CYCLOOXYGENASE-2 IN THE BIOACTIVATION OF DAPSONE AND SULFAMETHOXAZOLE
Vyas, P. M., Roychowdhury, S., & Svensson, C. K. (2005) · Drug Metabolism and Disposition · doi:10.1124/dmd.105.006890 · Cited by 12
Reinhart, J. M., Rose, W. E., Panyard, D. J., Newton, M. A., Liebenstein, T., Yee, J. S., & Trepanier, L. A. (2018) · Pharmacology Research & Perspectives · doi:10.1002/prp2.388 · Cited by 11
Racine, C. R., Ferguson, T., Preston, D. L., Ward, D. B., Ball, J. G., Anestis, D. K., Valentovic, M. A., & Rankin, G. O. (2016) · Toxicology · doi:10.1016/j.tox.2016.01.006 · Cited by 11
Pharmacogenetics and blood dyscrasias
Spielberg, S. P. (1996) · European Journal Of Haematology · doi:10.1111/j.1600-0609.1996.tb01653.x · Cited by 11
Self-citationLü, Y., Gong, Z., Xie, Y., Pan, J., Sun, J., Li, Y., Chen, S., Li, Y., Wang, Y., & Huang, Y. (2016) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2016/6194206 · Cited by 10
Adeyanju, K., Bend, J. R., Rieder, M. J., & Dekaban, G. A. (2018) · Virology Journal · doi:10.1186/s12985-018-0991-x · Cited by 10
A Comparison of the Effect of Five Phenothiazines on Hepatic CYP Isoenzymes in Rats
Tateishi, T., Kumai, T., Watanabe, M., Tanaka, M., & Kobayashi, S. (1999) · Pharmacology & Toxicology · doi:10.1111/j.1600-0773.1999.tb02018.x · Cited by 10
Hess, D. A., Bird, I. A., Almawi, W. Y., & Rieder, M. J. (1997) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)36616-9 · Cited by 10
Freund, Y. R. (2000) · Toxicological Sciences · doi:10.1093/toxsci/55.2.335 · Cited by 10
Cytochrome P450 isoform-specific in vitro methods to predict drug metabolism and interactions
Taavitsainen, P. (2001) · Cited by 9
Extrahepatic Targets and Cellular Reactivity of Drug Metabolites
Orhan, H. (2014) · Current Medicinal Chemistry · doi:10.2174/0929867321666140826113716 · Cited by 10
Valoti, M., Frosini, M., Palmi, M., Matteis, F. D., & Sgaragli, G. (1998) · Journal of Pharmacy and Pharmacology · doi:10.1111/j.2042-7158.1998.tb06915.x · Cited by 9
Sanderson, J. P., Hollis, F. J., Maggs, J. L., Clarke, S. E., Naisbitt, D. J., & Park, B. K. (2008) · Drug Metabolism and Disposition · doi:10.1124/dmd.108.021246 · Cited by 8
de Boer, S. R., Sastre, D., Castillo, A., Méndez, S. B., Hollmann, F., Lores, M., Schäffer, A., & Moreira, M. T. (2025) · Journal of environmental chemical engineering · doi:10.1016/j.jece.2025.115795 · Cited by 8
Trimethoprim/Sulfamethoxazole Does Not Affect the Steady‐State Disposition of Indinavir
Sturgill, M. G., Seibold, J. R., Boruchoff, S. E., Yeh, K. C., Haddix, H., & Deutsch, P. (1999) · The Journal of Clinical Pharmacology · doi:10.1177/00912709922011737 · Cited by 8
Comment: sulfonamide cross-reactivity: fact or fiction?
Phillips, E. J., & Knowles, S. R. (2005) · Annals of Pharmacotherapy · doi:10.1345/aph.1e350a · Cited by 8
Lehmann, D. F., Newman, N. B., & Morse, P. (1998) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1998.tb04454.x · Cited by 7
Kong, D., Li, Q., Zhang, P., Zhang, W., Yaqin, Z., & Ren, L. (2015) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2015.06.022 · Cited by 6
Drug hypersensitivity reactions in patients with HIV disease
Pirmohamed, M., Drummond, N. S., Naisbitt, D. J., & Park, B. K. (2007) · Expert Review of Clinical Immunology · doi:10.1586/1744666x.3.3.395 · Cited by 6
Towards the development of mechanism-based biomarkers to diagnose drug hypersensitivity
Durán‐Figueroa, N., Badillo-Corona, J. A., Naisbitt, D. J., & Castrejón-Flores, J. L. (2015) · Toxicology Research · doi:10.1039/c4tx00238e · Cited by 6
Bedard, K., Fuentealba, I. C., & Cribb, A. E. (2000) · Toxicology · doi:10.1016/s0300-483x(00)00169-4 · Cited by 6
Self-citationYamaguchi, Y., Kirita, S., Baba, T., Aoyama, J., Touchi, A., Tukey, R. H., Guengerich, F. P., & Matsubara, T. (1997) · PubMed · Cited by 6
T Cell Responses to Drugs and Drug Metabolites
Earnshaw, C. J., Pecaric-Petkovic, T., Park, B. K., & Naisbitt, D. J. (2013) · Proceedings of the Fourth International Symposium on Polarization Phenomena in Nuclear Reactions · doi:10.1007/978-3-0348-0726-5_10 · Cited by 6
The effect of repeat administration of GTS-21 on mixed-function oxidase activities in rat
Azuma, R., Komuro, M., Black, S. R., & Mathews, J. M. (1999) · Toxicology Letters · doi:10.1016/s0378-4274(99)00150-2 · Cited by 5
Pressiat, C., Mea-Assande, V., Yonaba, C., Tréluyer, J., Dahourou, D. L., Amorissani‐Folquet, M., Blanche, S., Eboua, F. T., Ye, D., Lui, G., et al. (2017) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.13397 · Cited by 6
Lehmann, D. F., Holohan, P. D., & Blair, D. C. (1996) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1996.tb04169.x · Cited by 5
Cribb, A. E., McQuaid, T., & Renton, K. W. (2001) · Biochemical Pharmacology · doi:10.1016/s0006-2952(01)00691-8 · Cited by 5
Self-citationVélez, A. M. A., Klein, D., Smoller, B. R., MD., M., & Howard, M. S. (2011) · North American Journal of Medical Sciences · doi:10.4297/najms.2011.382 · Cited by 4
Gasasira, A. F. (2010) · eScholarship (California Digital Library) · Cited by 4
Zhang, L., Chen, D., Xia, X. Y. X. Y., Yip, C., Rieder, M. J., & Bend, J. R. (2015) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.18433/j3sp5w · Cited by 3
Hypersensitivity adverse drug reactions in children: Pathophysiology and therapeutic implications
Rieder, M. J. (2001) · Current Therapeutic Research · doi:10.1016/s0011-393x(01)80095-3 · Cited by 3
Comparative pharmacokinetics of trimethoprim–sulfadiazine and trimethoprim–sulfamethoxazole in dogs
Ekstrand, C., Löwgren, M., Erkas, M., Devreese, M., Baere, S. D., Vo-Thanh, J., & Ferran, A. A. (2026) · BMC Veterinary Research · doi:10.1186/s12917-026-05604-7 · Cited by 2
Pathophysiologic Mechanisms of Immune-mediated Drug Hypersensitivity Reactions to Sulfonamides
Sultan, E. A. (2015) · Scholarship@Western (Western University) · Cited by 2
Hepatic expression profiles in retroviral infection: relevance to drug hypersensitivity risk
Wong, Y. Y., Johnson, B. P., Friedrich, T. C., & Trepanier, L. A. (2017) · Pharmacology Research & Perspectives · doi:10.1002/prp2.312 · Cited by 2
Hernández-Verdín, I., Ganelón-Ríos, A., Pettet-Ruiz, G., Sánchez-Garza, M., Reinoso-Reyes, J., & López‐Revilla, R. (2019) · Meta Gene · doi:10.1016/j.mgene.2019.100574 · Cited by 2
Sulfonamide-induced cutaneous drug reactions
Vyas, P. M. (2006) · doi:10.17077/etd.rttumisz · Cited by 2
Lanphier, R. M., Latham, B. D., Gerringer, A. J., Interrante, T., Jones, C. D., De Buysscher, T., Fallon, J. K., & Jackson, K. D. (2025) · Drug Metabolism and Disposition · doi:10.1016/j.dmd.2025.100195 · Cited by 1
Study on herb-drug interactions
Yang, L. L. (2011) · RMIT Research Repository (RMIT University Library) · doi:10.25439/rmt.27333027 · Cited by 1
Grillo, M. P. (2008) · doi:10.1002/9780470439265.ch22 · Cited by 1
Grillo, M. P. (2010) · Pharmaceutical Sciences Encyclopedia · doi:10.1002/9780470571224.pse121 · Cited by 1
Grillo, M. P. (2022) · doi:10.1002/9781119851042.ch20 · Cited by 1
Xia, W. (2002) · Työväentutkimus Vuosikirja
Ju, C. H. (1999) · Library and Archives Canada (Government of Canada)
Dijkstra, J. A. (2017) · University of Groningen research database (University of Groningen / Centre for Information Technology)
Metabolisms of Foreign Compounds
Chen, C. (2020) · Springer eBooks · doi:10.1007/978-3-030-41679-9_4
ATTENUATION OF OXIDATIVE AND NITROSATIVE STRESS BY PURE CONSTITUENTS OF TRADITIONAL CHINESE REMEDIES
Zhang, L. (2011) · Scholarship@Western (Western University)
(1996) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1996.tb16425.x
Pathomechanisms of Drug Hypersensitivity Targeting the Liver and Skin
Thomson, P., Naisbitt, D. J., & Ogese, M. O. (2022) · Springer eBooks · doi:10.1007/978-3-030-82743-4_6
François, M. O., Tah, C. F., Oscar, A. F., Abakar, M. N. A., Joseph, L., Otchom, B. B., & Mbacham, W. F. (2025) · Journal of Drug Delivery and Therapeutics · doi:10.22270/jddt.v15i5.7154
Wang, M., Li, C., Fu, X., Wang, F., Zhou, X., Zhang, B., Xu, W., Liang, L., Lei, Z., Qu, H., et al. (2026) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-026-04019-5
Arenas, D. C. V., Mantilla, S. S., Rodríguez, A. P., & Ávila, L. M. S. (2025) · Revista Ciencias Biomédicas · doi:10.32997/rcb-2025-5949
Seomun, S., & Yoo, S. (2026) · Computational and Structural Biotechnology Journal · doi:10.34133/csbj.0184
Model-Based Evaluation of the Warfarin–Sulfamethoxazole Drug–Drug Interaction
Takeda, K., Hirai, T., Okamoto, K., Sugioka, A., Okada, A., & Shibata, N. (2026) · European Journal of Drug Metabolism and Pharmacokinetics · doi:10.1007/s13318-026-01041-x
Metadata
- Authors
- Cribb, A. E., Spielberg, S. P., & Griffin, G. P.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- ORCID
- Cribb, A E
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 1995-03
- Volume
- 23
- Issue
- 3
- Pages
- 406-414
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W1743904312
- Cited by
- 169
- References
- 0
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 1 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 6 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 5 · 2014: 7 · 2013: 2 · 2012: 6
- FWCI
- 6.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Pharmacology (medical) › Drug-Induced Adverse Reactions
- Keywords
- sulfamethoxazole, CYP2C6, CYP2C9, CYP3A, CYP2B, liver microsomes, drug metabolism, phenobarbital induction, tolbutamide, sulfaphenazole, hydroxylamine reductase, troleandomycin, sulfonamide hypersensitivity
- MeSH terms
- Animals, Cytochrome P-450 Enzyme System, Humans, Hydroxylation, Male, Microsomes, Liver, Oxidation-Reduction, Sulfamethoxazole, Rats, Sprague-Dawley, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review