Effects of the anticancer dehydrotarplatin on cytochrome P450 and antioxidant enzymes in male rat tissues.
The effect of dehydrotarplatin (DTP), a new antineoplastic drug analogous to cisplatin, and its metabolite (Triacid) on the hepatic, renal and testicular CYP and antioxidant enzymes of male rats was investigated. The rats were treated i.p. with a single dose of DTP (25 mg kg(-1) day(-1)) or Triacid (17.5 mg kg(-1) day(-1)) and analysed 3 or 7 days post treatment. Three days after treatment, both drugs reduced body and liver weights, which partially recovered the control level after 7 days. DTP and, to a less extent, Triacid caused a depletion of plasmatic testosterone content and a down regulation in the liver of androgen dependent male specific CYP 2C11, but not of CYP 1A and 2E1, as determined by a significant decrease of 2alpha- and 16alpha-testosterone hydroxylase activities (markers for CYP 2C11) and of apoprotein immunoreactive with anti-rat CYP 2C11 antibodies. However, the activity of testicular 17alpha-progesterone hydroxylase, a key reaction in steroidogenesis, was not altered by these drugs. The DTP and Triacid administration did not cause any alteration of the plasmatic urea nitrogen and creatinine, known as markers of kidney toxicity. However, treatment with DTP, not Triacid, either 3 and 7 days post treatment, caused in the kidney microsomes a significant increase of the total CYP content, the CYP 4A-dependent (omega)- and (omega - 1)-lauric acid hydroxylase activities and apoprotein immunoreactive with anti-rat CYP 4A1. The present study also examined the enzymatic antioxidant status of kidney and liver. Neither DTP nor Triacid administration induced, with respect to control values, any alteration of hepatic and renal glutathione reductase, glutathione S-transferase, catalase, superoxide dismutase activities, hepatic GSH level and renal microsomal lipid peroxidation level. Among the antioxidant enzymes assayed, only the renal activity of glutathione peroxidase was significantly increased after DTP but not Triacid treatment. These results indicate that DTP at a dose of 25 mg/kg and Triacid cause a feminization of the CYP enzymes in male rat liver similar to that reported for cisplatin when administered at a low dose (5 mg/kg). However, unlike cisplatin, DTP and its metabolite were unable to enhance BUN and creatinine and cause any depression of CYP activities and antioxidant enzymes in the kidney, suggesting that DTP may have low or even no potential in inducing nephrotoxicity.
Nannelli
Annalisa
A
Istituto di Fisiologia Clinica, Area della Ricerca CNR, via Moruzzi 1, 56100 Pisa, Italy.
Messina
Andrea
A
Marini
Sandra
S
Trasciatti
Silvia
S
Longo
Vincenzo
V
Gervasi
Pier Giovanni
PG
D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D000975:Antioxidants / Q000378:metabolism*; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006900:Hydroxylation; D007527:Isoenzymes / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007850:Lauric Acids / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D013737:Testis / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013739:Testosterone / Q000097:blood / Q000378:metabolism
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D000975:Antioxidants; D007527:Isoenzymes; D007850:Lauric Acids; D009944:Organoplatinum Compounds; C524314:dehydrotarplatin; C030358:lauric acid; D013739:Testosterone; D011374:Progesterone; D003577:Cytochrome P-450 Enzyme System; D003404:Creatinine; C023650:aniline