Hepatocarcinogens induce gene mutations in rats in fibroblast-like cells from a subcutaneous granulation tissue

Abstract

'To whom reprint requests should be sent Gene-mutations at the 6-thioguanine locus, in Hbroblast likecells rapidly proliferating on the inside of rat subcutaneous air pouches were analysed (Granuloma Pouch Assay). Target cells were exposed directly by injection into the air pouch, or systemicaliy by oral or intraperitoneal administration to three hepatocarcinogens aflatoxin B,, 2-acetyIaminofluorene (2-AAF) and vinylchloride. In addition ethylnitrosourea (ENU) was used as a positive control, and 2-aminofluorene to characterize the pharmacokinetic behaviour of 2-AAF. When administered directly, all chemicals except 2-AAF induced a dose-dependent increase in gene-mutation frequencies. However, 2-AAF was mutagenic after oral administration. The highest inducible mutation frequencies found with the hepatocarcinogens were 8 to 10 times the spontaneous mutation frequency, but only ~ 10% of that found with the control mutagen ENU. The known enzymic activation capacity of the granulation tissue, and the mutagenic activity of other chemicals in this system already reported, suggest that after direct exposure, the prostaglandin H synthetase pathway or lipoxygenases are involved in the activation of the hepatotoxins to gene mutation inducing species in vivo. 2-AAF seems to be converted via stable intermediates to the ultimate mutagenic species in the extrahepatic target tissues.

Inflammation as a Cancer Co-Initiator: New Mechanistic Model Predicts Low/Negligible Risk at Noninflammatory Carcinogen Doses

“…33,40,43–45 The AFB 1 -DNA adducts in turn induce mutations and (with possibly greater potency) mitotic recombination in roughly linear proportion to adduct load. 46–49 The MVK model fit to male rat HCC data thus presumed that: (1) AFB 1 acted to increase (for simplicity, equal) first and second mutation rates ν ( t ) and μ ( t ) (see Appendix A) over their background values in the absence of such exposure by an equal magnitude F proportional to dose both during and (because of AFB 1 -FAPY adduct persistence) after AFB 1 exposure and (2) CDDO-Im acted to reduce F to values f 2 F and f 3 F during and after AFB 1 exposure, respectively, using corresponding fractions f 2 = 0.31 and f 3 = 0.40 measured by Johnson et al 20 for liver AFB 1 -FAPY adducts in rats co-administered CDDO-Im relative to adducts measured, respectively, during those 2 periods. Additionally, to minimize HCC incidence predicted under the AFB 1 + CDDO-Im protocol under assumptions plausibly consistent with MSM theory implemented by an MVK model, it was assumed that during AFB 1 exposure CDDO-Im acted on premalignant cells to reduce their birth rate b ( t ) 1000-fold and increase their death rate d ( t ) 10-fold relative to these rates without CDDO-Im co-exposure.…”

“…33,40,[43][44][45] The AFB 1 -DNA adducts in turn induce mutations and (with possibly greater potency) mitotic recombination in roughly linear proportion to adduct load. [46][47][48][49] The MVK model fit to male rat HCC data thus presumed that:…”

Genotoxicity of aniline derivatives in various short-term tests

“…This might explain why the positive results of MOCA could not be reproduced in a second experiment. The decrease of mutagenicity at high dose Ievels in the thioguanine test can be explained by the possible interference of anilines with prostaglandin synthesis which in turn affects DNA synthesis and mutation fixation (Maier and Schawalder, 1988).…”

Differences in the response to oxidative stress and mutant frequency in CD (Sprague-Dawley) and Fisher 344 rats due to an induced inflammatory response

“…E-mail: rsams@nctr.fda.gov al., 1981]. The air pouch can also be used as a model system in which relative frequencies of genetic and preneoplastic changes induced in vivo can be monitored in the fibroblasts lining the pouch [Maier, 1984[Maier, , 1988Jansen et al, 1994]. Formation of the air pouch is accomplished by subcutaneous injection of sterile air in the scapular region of a rodent.…”

“…Formation of the air pouch is accomplished by subcutaneous injection of sterile air in the scapular region of a rodent. This causes a mechanical stretching of the cells that stimulates proliferation and increases the sensitivity of mutation detection for agents administered systemically or directly into the pouch [Maier, 1984[Maier, , 1988Jansen et al, 1994]. Thus, this model allows investigation of the processing of DNA damage produced by oxidative stress in addition to assessment of the level of initial DNA damage.…”