Drug stimulation of δ aminolevulinic acid synthetase and cytochrome P 450 in vivo in chick embryo liver
Cytochrome P-450 Enzyme System
The utility of the chick embryo as a model system for the simple screening in vivo of drug effects on δ aminolevulinic acid synthetase (ALAS) was examined and demonstrated. The chick embryo was shown to be capable of drug stimulation of ALAS at least as early as eight days before hatching and, in contrast to other species, to undergo a marked increase in that capacity during the few days prior to hatching. Fifty one drugs, most of which are in common clinical use, were studied for their effect on ALAS. Drug stimulation of ALAS in vivo reported here and stimulation of hepatic porphyrin formation in vivo or in cultured liver cells as shown by others were well correlated (100% and 85%, respectively). Thus, the ability of a large number of drugs to stimulate porphyrins is related to their ability to increase the in vivo activity of ALAS. Ten drugs, including aminoglutethimide, diazepam, ethosuximide, ethotoin, o,p' DDD, paraldehyde, paramethadione, pargyline HCl, pentylenetetrazole and tranylcypromine sulfate were newly identified as inducers of hepatic ALAS. Six drugs which stimulated ALAS also increased the hepatic content of cytochrome P 450. However, variations in the length of time required for maximal stimulation of ALAS and cytochrome P 450 by different drugs were shown and trimethadione and phenylbutazone, at doses which stimulated hepatic ALAS, decreased the cytochrome P 450 content of liver. Phenobarbital, diphenylhydantoin and phenylbutazone all caused parallel alterations of similar degree in hepatic cytochrome P 450 content and aminopyrine demethylase activity, which indicates that in the chick embryo as in other species studied, those two activities are related.