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>
Catalysis of the cysteine conjugation and protein binding of acetaminophen by microsomes from a human lymphoblast line transfected with the cDNAs of various forms of human cytochrome P450
activation; ethanol; hepatic microsomes; hepatocytes; inhibitors; monoclonal-antibodies; oxidation; para-benzoquinone imine; Pharmacology & Pharmacy; rat-liver; reactive metabolite formation
We have previously found that for acetaminophen kinetic differences exist between the hepatic microsomal catalyzed protein binding and cysteine conjugation. We have also observed that the protein binding of acetaminophen is only to intralumenal proteins. Together these data suggested that two pools of the reactive metabolite, N-acetyl-p-benzoquinone imine (NABQI), are formed during the oxidative metabolism of acetaminophen: one on the cytosolic surface and the other within the lumen of the microsomes. This would indicate that some of forms of cytochrome P450 (CYP) catalyzing NABQI formation have their active site on the cytosolic surface and others on the lumenal surface. We have examined this question by comparing the rates of cysteine conjugation and protein binding of acetaminophen by microsomes from lymphoblasts tranfected with the cDNAs for human CYPs. We found that CYP2D6 catalyzed only cysteine conjugation; CYP1A2 and 3A4 catalyzed only protein binding; CYP2E1 catalyzed both; and CYP1A1, CYP2A6 and CYP2B6 catalyzed neither. These data suggest that CYP2D6 has its active site only on the cytosolic surface; CYP1A2 and CYP3A4 only on the lumenal surface; and CYP2E1 has catalytic sites on both the lumenal and cytosolic surfaces of the membrane. In mouse studies we have found that ethanol administration increased acetaminophen protein binding by 265% but cysteine conjugation by only 61%. CYP2E1 and CYP2B increased, whereas CYP3A decreased and the others did not change. These data suggest that in control mice CYP2E1 catalyzes the bulk of protein binding, whereas CYP2D catalyzes slightly more cysteine conjugation than does CYP2E1.
Zhou L X; Erickson R R; Hardwick J P; Park S S; Wrighton S A; Holtzman J L
Journal of Pharmacology and Experimental Therapeutics
1997
1997-05
Journal Article
n/a
Phenytoin metabolism by the gingiva of normal humans: The possible role of reactive metabolites of phenytoin in the initiation of gingival hyperplasia
General & Internal Medicine; Research & Experimental Medicine
Zhou L X; Pihlstrom B; Hardwick J P; Park S S; Wrighton S A; Holtzman J L
Journal of Investigative Medicine
1996
1996-09
Journal Article
n/a
Phenytoin Metabolism By Gingiva From Normal Humans
Pharmacology & Pharmacy
Holtzman J L; Zhou L X; Pihlstrom B; Hardwick J P; Park S S; Wrighton S A
Clinical Pharmacology & Therapeutics
1997
1997-02
Journal Article or Conference Abstract Publication
n/a