Specificity and inducibility of the metabolic reduction of chromium(VI) mutagenicity by subcellular fractions of rat tissues.
The mutagenicity of sodium dichromate in the Ames test was decreased as a consequence of chromium(VI) reduction by tissue postmitochondrial (S-9 or S-12) fractions from untreated rats with the following rank of efficiency: liver; kidney; and lung. The effects of lung preparations were significantly enhanced following the intratracheal administration of high doses (0.25 mg/kg) of dichromate itself, 5 times per week for 4 weeks (i.e., 20 fractionated instillations). No changes were conversely detected following single weekly doses of 1.25 mg/kg for the same period (i.e., four cumulative instillations). The local stimulation of chromium(VI) metabolism was also confirmed by testing the mutagenicity of calcium chromate and chromium trioxide, whereas the metabolism of a number of other activatable or deactivatable mutagens was not significantly affected by intratracheal treatment with chromium(VI). Of three enzyme inducers injected i.p. which modified the spectral properties and/or concentration of cytochromes P-450 in liver and lung microsomes, only Aroclor 1254 proved to stimulate chromium(VI) metabolism in lung cells. In liver cells, Aroclor 1254 and to a lower extent phenobarbital induced chromium(VI) reduction, while 3-methylcholanthrene was ineffective. Pretreatment of rats with these three compounds resulted in a selective induction of the metabolic activation of promutagens [benzo(a)pyrene and its trans-7,8-diol, 2-aminofluorene, aflatoxin B1] and of the metabolic deactivation of direct-acting mutagens [2-methoxy-6-chloro-9-[3-(2-chloroethyl)-aminopropylamino] acridine X 2HCl, epichlorohydrin, 4-nitroquinolino-N-oxide] by S-12 and microsomal fractions. These findings indicate that, in addition to already recognized detoxification mechanisms operating outside target cells (26), specific and inducible chromium-reducing pathways, mediating threshold phenomena in chromium carcinogenesis, do also occur in the intracellular environment.
D000818:Animals; D002857:Chromium / Q000378:metabolism* / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009153:Mutagens / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D011506:Proteins / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains
D009153:Mutagens; D011506:Proteins; D002857:Chromium; D003577:Cytochrome P-450 Enzyme System