Metabolism of phenytoin by the gingiva of normal humans: The possible role of reactive metabolites of phenytoin in the initiation of gingival hyperplasia
clinical report; cyclosporine-a; cytochrome P450; enlargement; hepatotoxicity; microsomes; monoclonal-antibodies; overgrowth; Pharmacology & Pharmacy; proteins; severity
Gingival hyperplasia is a well-known complication of therapy with cyclosporine, calcium channel blockers, and phenytoin, It is characterized by the presence of inflammation and a marked fibrotic response. The mechanism of this adverse reaction is unknown, We propose that it may be initiated by the metabolic activation of these drugs to form reactive metabolites, These then cause cellular injury and lead to the gingival hyperplasia, To evaluate this hypothesis we examined phenytoin metabolism and the cytochrome P450 contents of gingival tissues from 10 patients undergoing surgery for various periodontal conditions, We found that microsomes obtained from the gingiva show significant phenytoin hydroxylase activity as determined by the production of 5-(4'-hydroxyphenyl)-5-phenylhydantoin (HPPH) (range, 12.8 pmol HPPH/min . mg microsomal protein to 276.9 pmol HPPH/min . mg microsomal protein; rat control, 133.7+/-11.5 pmol HPPH/min . mg microsomal protein), We also found that CYP1A1, CYP1A2, CYP2C9, CYP2E1, and CYP3A4 were present in these microsomes, We detected no CYP2B6 or CYP2D6. We believe that these data support our hypothesis that the proliferative inflammation observed with drugs such as phenytoin, nifedipine, and cyclosporine may be initiated by the formation of reactive metabolites and that the formation of these metabolites may be catalyzed by one or more CYPs found in the gingiva, These metabolites may then cause cellular injury and induce a reactive inflammatory response, followed by fibroblastic proliferation, This proliferation leads to the excess collagen deposition observed with gingival hyperplasia.
Zhou L X; Pihlstrom B; Hardwick J P; Park S S; Wrighton S A; Holtzman J L
Clinical Pharmacology & Therapeutics
1996
1996-08
Journal Article
<a href="http://doi.org/10.1016/s0009-9236(96)90135-6" target="_blank" rel="noreferrer noopener">10.1016/s0009-9236(96)90135-6</a>
Targeted Liquid Chromatography-mass Spectrometry Analysis Of Serum Acylcarnitines In Acetaminophen Toxicity In Children
-oxidation; acetaminophen; acute liver-failure; acylcarnitine; biomarker; clinical; clofibrate; hepatic; hepatotoxicity; induced; induced hepatic-necrosis; metabolism; metabolomics; mice; multicenter; overdose; protein adducts; Research & Experimental Medicine; toxicity
Bhattacharyya S; Yan K; Pence L; Simpson P M; Gill P; Letzig L G; Beger R D; Sullivan J E; Kearns G L; Reed M D; Marshall J D; Van Den Anker J N; James L P
Biomarkers in Medicine
2014
2014-02
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.2217/bmm.13.150" target="_blank" rel="noreferrer noopener">10.2217/bmm.13.150</a>
Targeted Liquid Chromatography-mass Spectrometry Analysis Of Serum Acylcarnitines In Acetaminophen Toxicity In Children
-oxidation; acetaminophen; acute liver-failure; acylcarnitine; biomarker; clinical; clofibrate; hepatic; hepatotoxicity; induced; induced hepatic-necrosis; metabolism; metabolomics; mice; multicenter; overdose; protein adducts; Research & Experimental Medicine; toxicity
Aim: Long-chain acylcarnitines have been postulated to be sensitive biomarkers of acetaminophen (APAP)-induced hepatotoxicity in mouse models. In the following study, the relationship of acylcarnitines with other known indicators of APAP toxicity was examined in children receiving low-dose (therapeutic) and high-dose (overdose' or toxic ingestion) exposure to APAP. Materials & methods: The study included three subject groups: group A (therapeutic dose, n = 187); group B (healthy controls, n = 23); and group C (overdose, n = 62). Demographic, clinical and laboratory data were collected for each subject. Serum samples were used for measurement of APAP protein adducts, a biomarker of the oxidative metabolism of APAP and for targeted metabolomics analysis of serum acylcarnitines using ultra performance liquid chromatography-triple-quadrupole mass spectrometry. Results: Significant increases in oleoyl- and palmitoyl-carnitines were observed with APAP exposure (low dose and overdose) compared with controls. Significant increases in serum ALT, APAP protein adducts and acylcarnitines were observed in overdose children that received delayed treatment (time to treatment from overdose >24 h) with the antidote N-acetylcysteine. Time to peak APAP protein adducts in serum was shorter than that of the acylcarnitines and serum ALT. Conclusion: Perturbations in long-chain acylcarnitines in children with APAP toxicity suggest that mitochrondrial injury and associated impairment in the -oxidation of fatty acids are clinically relevant as biomarkers of APAP toxicity.
Bhattacharyya S; Yan K; Pence L; Simpson P M; Gill P; Letzig L G; Beger R D; Sullivan J E; Kearns G L; Reed M D; Marshall J D; Van Den Anker J N; James L P
Biomarkers in Medicine
2014
2014-02
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.2217/bmm.13.150" target="_blank" rel="noreferrer noopener">10.2217/bmm.13.150</a>