Interspecies variations in fatty acid hydroxylations involving cytochromes P450 2E1 and 4A.
The liver microsomal fractions of seven mammalian species including rat, dog, monkey, hamster, mouse, gerbil and humans, catalyzed the hydroxylation of saturated (lauric, myristic and palmitic) and unsaturated (oleic and linoleic) fatty acids to the corresponding omega and (omega-1)-hydroxylated derivatives, while stearic acid was not metabolized. Lauric acid was the most efficiently hydroxylated, and the rank of catalytic activity was lauric > myristic > oleic > palmitic > linoleic. Among the mammalian species studied, mouse and hamster presented the highest level of fatty acid omega and (omega-1)-hydroxylases, while the lowest activity was observed in dog and monkey. In all the animal species, the (omega-1)-hydroxylation of fatty acids correlated significantly with the immunodetectable content of CYP2E1 and the 4-nitrophenol hydroxylation activity, known to be mediated by cytochrome P450 2E1. On the contrary, only the omega-hydroxylation of lauric acid slighly correlated with the level of cytochrome P450 4A, while no significant correlation was found with the omega-hydroxylation of the other fatty acids. Furthermore, chemical and immuno-inhibitions of the hydroxylations of fatty acids led to the conclusion that fatty acid (omega-1)-hydroxylase activity is catalyzed by P450 2E1 in all the mammalian species, while the fatty acid omega-hydroxylase activity may be catalyzed by cytochromes P450 from the 4A family. Therefore, lauric acid (omega-1)-hydroxylation along with 4-nitrophenol hydroxylation can be used as a specific and sensitive method to measure the level of CYP2E1 induction in humans and various animals.
Adas
F
F
Laboratoire de Biochimie-Nutrition, EA 948, Faculté de Médecine, Brest, France.
Berthou
F
F
Salaün
J P
JP
Dréano
Y
Y
Amet
Y
Y
D000477:Alkylating Agents / Q000378:metabolism; D000478:Alkylation; D000818:Animals; D006224:Cricetinae; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D005227:Fatty Acids / Q000378:metabolism*; D005849:Gerbillinae; D000882:Haplorhini; D006801:Humans; D006900:Hydroxylation; D015151:Immunoblotting; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009603:Nitroso Compounds / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D000477:Alkylating Agents; D005227:Fatty Acids; D009603:Nitroso Compounds; C008651:4-nitrosodimethylaniline; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D042926:Cytochrome P-450 CYP4A