Sex-specific induction of mutations by PhIP in the kidney of male and female rats and its modulation by conjugated linoleic acid.

The heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a recognized mutagen and carcinogen in the colon and prostate of male rats and in the mammary gland of female rats. In the current study, we examined the mutagenicity of PhIP in the kidney of male and female lacI transgenic rats and its modulation by a dietary chemopreventive agent, conjugated linoleic acid (CLA). Sex-specific changes in mutation were observed following PhIP and CLA treatment. Exposure to 100 ppm PhIP through dietary supplementation for 47 days induced a lacI mutation frequency (MF) of 7.7 +/- 0.3 x 10(-5) and 4.7 +/- 1.0 x 10(-5) in the kidney of male and female rats, respectively. The PhIP-induced MFs in the kidney of male and female rats were significantly different from each other and were 300% (P < 0.001) and 60% (P < 0.05) higher than the corresponding controls, respectively. When rats were given CLA along with PhIP, CLA completely inhibited the formation of PhIP-induced mutations in the kidney of female rats, but not in male rats. Comparison of mutational spectra did not detect significant differences between male rats treated with PhIP and PhIP + CLA. However, unlike the -1 frameshifts induced by PhIP in the colon and prostate, which consist primarily of G:C deletions, -1 frameshifts in the kidney involved the loss of both G:C and A:T basepairs. Our data indicate that the kidney of the rats responds in a sex-dependent way to mutagenesis and antimutagenesis by PhIP and CLA. These differences may be related to hormonally regulated induction of P450 enzymes or cell proliferation. Copyright 2002 Wiley-Liss, Inc.