Renal metabolism of acrylonitrile to cyanide: in vitro studies.
Acrylonitrile (VCN) is a widely used industrial chemical. The present work examines the mechanism of its renal toxicity. In renal centrifugal fractions from Sprague-Dawley rats, the metabolism of VCN to cyanide (CN(-)) was highest in the microsomal fraction and required a NADPH-generating system in the presence of magnesium ions for maximum activity. This biotransformation of VCN to CN(-)was characterised with respect to time (15 min), microsomal protein concentration (3 mg ml(-1)), pH (7.5) and temperature (37 degrees C). The V(max)of the reaction was 118.2 pmol CN(-)mg(-1)protein min(-1)and K(m)was 160.2 micromol VCN. Activation of VCN to CN(-)was markedly increased in microsomes obtained from phenobarbital (PB), ethanol, 4-methylpyrazole and 3-methylcholanthrene-treated rats by 161.5, 89.6, 71.0 and 50.2%, respectively. Addition of SKF 525-A (5x10(-4)m) or benzimidazole (2 m m) to the incubation mixtures significantly inhibited VCN metabolism by 66.6 and 78.8%, respectively. VCN metabolism to CN(-)was enhanced significantly by the addition of 10 m m of glutathione (GSH), l -cysteine, d -penicillamine, cysteamine or 2-mercaptoethanol to 389.5, 886.5, 611. 1, 145.5 and 384.0% of control, respectively. These findings indicate that VCN is metabolised in the kidney via cytochrome P-450-dependent mixed function oxidase system. 1999 Academic Press.
Mostafa
A M
AM
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt.
Abdel-Naim
A B
AB
Abo-Salem
O
O
Abdel-Aziz
A H
AH
Hamada
F M
FM
D000181:Acrylonitrile / Q000378:metabolism*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D003486:Cyanides / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology; D000077604:Fomepizole; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009249:NADP / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013696:Temperature
D001562:Benzimidazoles; D003486:Cyanides; D011720:Pyrazoles; D013438:Sulfhydryl Compounds; D000431:Ethanol; D009249:NADP; D008748:Methylcholanthrene; D000077604:Fomepizole; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; C031000:benzimidazole; D000181:Acrylonitrile; D010634:Phenobarbital