Metabolic activation of aromatic hydrocarbons in purified rat liver nuclei: induction of enzyme activities and binding to DNA with and without monooxygenase-catalyzed formation of active oxygen.

Abstract

Purified rat liver nuclei covalently bound low levels of seven aromatic ['4C~hydrocarbons

Time course of the induction of aryl hydrocarbon hydroxylase in rat liver nuclei and microsomes by phenobarbital, 3-methylcholanthrene, 2,3,7,8-tetrachloro-dibenzo-p-dioxin, dieldrin and other inducers

“…In the beginning. the extent of AHH induction is significantly higher in the nuclear fraction, which is in agreement with Observations by otherauthors [9,14,16,17]. Afterprolongedadminis~ tration, however, the nuclear activity is reduced to an induction rate similar to the one found in the microsomes.…”

“…AHH holds a centrat place in the metabolism of foreign compounds and in the activation of chemical carcinogens to electrophilic metabolites, especially of PAH [4][5][6][7]. In mammalian liver, AHH is found in the ER, but also, with much Jess activity, in the outer membrane of the nucJeus, and the binding of P AH to protein and ON A can be catalyzed by microsomes as weH as by isolated nuclei (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). AHH can be induced by a variety of substances and it has been established that the extent of binding of PAH to protein and DNA in vitro is correlated to the induction of AHH in microsomes, nuclei or both [14,15,17,19].…”

“…In mammalian liver, AHH is found in the ER, but also, with much Jess activity, in the outer membrane of the nucJeus, and the binding of P AH to protein and ON A can be catalyzed by microsomes as weH as by isolated nuclei (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). AHH can be induced by a variety of substances and it has been established that the extent of binding of PAH to protein and DNA in vitro is correlated to the induction of AHH in microsomes, nuclei or both [14,15,17,19]. It has also been shown that the carcinogenic potency of different P AH is correlated with the extent of binding to DN A [20,21].…”

“…The extent of short-term induction of AHH activity was found tobe different in microsomes and nuclei and dependent on the inducer used [9,14,17] and the hypothesis was considered that the two compartments are under separate control. Due to the fact that the AHH activity found in the nucleus is much lower than the one found in the microsomal fraction much work was performed on microsomes but very Jittle on the nuclear AHH, of which onJy short term induction experiments have so far been published.…”

Differential effects of antioxidants, steroids and other compounds on benzo(a)pyrene 3-hydroxylase activity in various tissues of rat

“…The enzyme system responsible for this activation consists of a haemoprotein cytochrome P450, a flavoprotein NADPH-cytochrome P450 reductase and phospholipid (Lu et al, 1969). This enzyme systenm resides mainly in the microsomal fractions of several tissues (Wattenberg & Leong, 1962;Zampaglione & Mannering, 1973;Chhabra & Fouts, 1974) but has also been shown to be active in the nuclear fraction of rat liver (Khandwala & Kasper, 1973;Rogan et al, 1976). In vitro studies have shown that BP is metabolized to a complex array of metabolites which include arene oxides, phenols, quinones and dihydrodiols (Holder et al, 1974;kSelkirk et al, 1974;Sims & Grover, 1974).…”