Polychlorinated biphenyls increase fatty acid desaturation in the proliferating endoplasmic reticulum of pigeon and rat livers

Abstract

1. Polychlorinated biphenyls (PCB) are abundant and persistent pollutants in the ecosystem. Commercial mixtures (e.g. Aroclor 1254) can contain up to 80 different isomers and congeners, many of which accumulate in biological systems by the ingestion of PCB-contaminated lipid components of food chains.2. Commercial mixtures of PCB induce, in hepatic microsomal membranes in vivo, a variety of different forms of the cytochrome P-450 components of enzyme systems involved in the metabolism of drugs and other xenobiotics, and can also induce the proliferation of this membrane. Since these microsomal enzyme systems share a number of the requirements of microsomal fatty acid desaturases, we have investigated whether the induction by PCB in vivo of cytochrome-P-450-linked enzymes in the proliferating hepatic microsomal membrane of the pigeon and the rat is accompanied by increased proportions of polyunsaturated fatty acids in t h s membrane.3. The most striking changes observed 120 h after treating pigeons and rats with 1.5 mmol Aroclor 1254/kg body mass were 2.2-fold and 1.6-fold increases, respectively, in the proportion of arachidonic acid in the hepatic microsomal membrane. When the effects of this treatment on the proliferation of this membrane and increase in liver mass are taken into account, the amount of arachidonic acid in the total microsomal membrane of pigeon and rat livers increased 6.7-fold and 1.9-fold, respectively.4. These changes were accompanied by very significant increases in pigeons and rats of the concentration of hepatic microsomal cytochrome P-450, and in the activity in microsomal protein of a wide range of cytochrome P-450-dependent enzyme involved in the metabolism of drugs and other xenobiotics.5. This effect of PCB, of increasing in vivo the degree of unsaturation of fatty acids of hepatic microsomal membrane, appears to be a novel finding, and does not seem to have been investigated for other drugs and xenobiotics. Preliminary results have shown that the effect is accompanied by substantial increases in the total activity of A s and A 5 microsomal fatty acid desaturases converting 18:2 (9, 12) (linoleic acid) to 20:4 (5, 8,11,14) (arachidonic acid) [Borlakoglu, J. T., Dils, R. R., Edwards-Webb, J. D. &Walker, C. H. (1988) Biochem. Soc. Trans. 16, 10721. 6. It is postulated that there is a significant link between increased fatty acid desaturation and the induction of cytochrome-P-450-linked enzymes, and this is discussed in terms of the mechanisms involved in the metabolism of foreign compounds.Polychlorinated biphenyls are abundant and persistent lipid-soluble pollutants in the ecosystem (see [1 -31 for reviews). Commercial mixtures (e.g. Aroclor 1254) may contain up to 80 different isomers and congeners, many of which accumulate in biological systems through ingestion of PCBcontaminated lipid components of food chains, and PCB are present in fatty tissues and blood of species at the apex of these chains [4, 51.

Cytochrome P450s and Short-chain Dehydrogenases Mediate the Toxicogenomic Response of PCB52 in the Nematode Caenorhabditis elegans

“…52,53 Arcolor 1254 was found to increase fatty acid desaturation in both rat and pigeon hepatic microsomes. 54 In particular, ortho-substituted PCBs were shown to alter membrane structure by an increased fluidity. 36,55 This process becomes manifested by, for example, the inhibition of lipase enzymes, as shown by Ferreira & Patton for the pancreatic lipase and biphenyl.…”

Proteasome inhibition compromises direct retention of cytochrome P450 2C2 in the endoplasmic reticulum

“…Thus, inhibition of proteasomal degradation can affect the composition of the ER membrane, which could then affect the mobility and distribution of ER proteins. Proliferation of the ER membranes, occurring during induction of P450 expression by drugs, also results in changes in membrane composition [14, 63]. So, it is possible that inhibition of proteasomal degradation affects ER retention of CYPs by indirectly modifying the ER membrane composition.…”

Fatty Acids, Lipids, and Cytochrome P-450 Monooxygenase in Hepatic Microsomes of Minks Fed Fish-Based Diets and Exposed to Aroclor 1242

“…Until now, the effects of PCBs on the fatty acid composition of mammalian endoplasmatic reticulum have been studied only in the rat and pigeon using a large dose given as a single injection (Narbonne et al, 1990;Borlakoglu et al, 1990aBorlakoglu et al, , 1991Matsusue et al, 1997). Although the results of the different studies are contradictory, the large changes in the fatty acid composition have been thought to be due to changed activities of fatty acid desaturases located on microsomal membranes.…”

“…The desaturases may actually be isoforms of the cytochrome P-450-dependent monooxygenase system (Borlakoglu et al, 1991). A large injected dose of PCBs (1.5 mmol/kg Aroclor 1254) increased the degree of unsaturation of the fatty acids in hepatic microsomes (Borlakoglu et al, 1990a), but also contradictory results, losses of PUFAs, have been published (Matsusue et al, 1997). In addition to increasing fatty acid desaturase activity, the activated P-450 system generates oxygen radicals and may cause oxidative stress (Saito, 1990;Vermeulen, 1996;Guengerich, 1996).…”