The biotransformation of p-xylene to a toxic aldehyde.
Rats given a single ip injection of p-xylene suffered 65% loss of pulmonary microsomal p-xylene hydroxylase activity. The activity was protected by pretreating the rats with phenobarbital, which increased hepatic p-xylene hydroxylase and cytosolic aldehyde dehydrogenase activities, but had no effect on alcohol dehydrogenase activity in hepatic cytosol. Pretreatment of rats with pyrazole caused a 60% inhibition of liver alcohol dehydrogenase but had no effect on liver aldehyde dehydrogenase activity. This treatment partially protected the pulmonary microsomal p-xylene hydroxylase from inactivation by p-xylene. Experiments in vitro showed that inactivation of cytochrome P-450 by p-xylene required the metabolic conversion of p-xylene to p-tolualdehyde. The reactive intermediate (p-tolualdehyde) required the presence of NADPH to carry out the inactivation. Inasmuch as lung tissues cannot form p-tolualdehyde (because of the low activity of p-methylbenzyl alcohol dehydrogenase), it is assumed that the inactivation of lung enzymes in vivo following exposure to p-xylene was due to the aldehyde intermediate which is formed in the liver and transported to the lung.
D000447:Aldehydes / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D003579:Cytochrome Reductases / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D008168:Lung / Q000648:ultrastructure; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013997:Time Factors; D014992:Xylenes / Q000378:metabolism*
D000447:Aldehydes; D011720:Pyrazoles; D014992:Xylenes; D006899:Mixed Function Oxygenases; D003579:Cytochrome Reductases