Activity of oxidative routes of metabolism of debrisoquin, mephenytoin, and dapsone is unrelated to the pathogenesis of vinyl chloride-induced disease.
The hypothesis, that cytochrome P4502D6, cytochrome P4502CMP, cytochrome P4503A4 or N-acetyl-transferase may form active intermediary metabolites that could be etiologically related to vinyl chloride-induced disease was investigated in 21 drug-free workers with previous development of vinyl chloride-induced disease and in 23 drug-free workers from the same plant who did not develop the syndrome. Each subject received simultaneous oral administration of debrisoquin (10 mg), mephenytoin (100 mg), and dapsone (100 mg). Measurement of the debrisoquin recovery ratio, the 8-hour recovery of 4-hydroxymephenytoin, and the dapsone recovery ratio in the subsequent 8-hour urine sample provided in vivo phenotypic indexes of cytochromes P4502D6, P4502CMP, and P4503A4 activity, respectively. An 8-hour blood sample was used to measure the acetylation ratio, a measure of N-acetyltransferase activity. The frequency distributions of each drug metabolizing activity were similar between groups. Within this small sample, there was no evidence to implicate cytochromes P4502D6, P4502CMP, and P4503A4 and N-acetyltransferase in the pathogenesis of vinyl chloride-induced disease.
Black
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Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tenn.
May
G
G
Csuka
M E
ME
Lupoli
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S
Wilkinson
G R
GR
Branch
R A
RA
D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003622:Dapsone / Q000378:metabolism*; D003647:Debrisoquin / Q000378:metabolism*; D006801:Humans; D008297:Male; D008617:Mephenytoin / Q000378:metabolism*; D008875:Middle Aged; D009784:Occupational Diseases / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D010641:Phenotype; D012044:Regression Analysis; D014752:Vinyl Chloride / Q000009:adverse effects*
D003622:Dapsone; D003577:Cytochrome P-450 Enzyme System; D001191:Arylamine N-Acetyltransferase; D008617:Mephenytoin; D014752:Vinyl Chloride; D003647:Debrisoquin