Dietary glycine protects from chemotherapy-induced hepatotoxicity.
Hepatotoxic side effects of neoadjuvant chemotherapy for colorectal liver metastases increase perioperative morbidity and mortality. Glycine protects liver from injury in various animal models. Thus, this study was designed to assess its effect on liver after chemotherapy. Sprague-Dawley rats (200-220 g) were fed a synthetic diet containing 5% glycine for 5 days. Subsequently, chemotherapy (FOLFIRI: irinotecan, folinic acid and fluorouracil, or FOLFOX: oxaliplatin, folinic acid and fluorouracil) was administered at standard doses. Transaminases, histology, immunohistochemistry and in vivo microscopy were used to index liver injury, to monitor intrahepatic microperfusion and activation of Kupffer cells. Glycine significantly decreased transaminases after chemotherapy to 25-50% of control values (p < 0.05). Microvesicular steatosis was significantly reduced from 18.5 ± 3.4 and 57.1 ± 8.6% in controls to 9.5 ± 1.8 and 37.7 ± 4.4% after FOLFIRI and FOLFOX, respectively. Furthermore, phagocytosis of latex beads was reduced by about 50%, while leukocyte adherence in central and midzonal subacinar zones decreased to 60-80% after glycine (p < 0.05). Glycine significantly reduced expression of inducible nitric oxide synthase after chemotherapy, while hepatic microcirculation was increased (p < 0.05). This study shows for the first time that glycine reduces chemotherapy-induced liver injury. The underlying mechanisms most likely include Kupffer cells and an improved intrahepatic microperfusion.
Mikalauskas
Saulius
S
Department of General and Transplantation Surgery, Ruprecht-Karls-University of Heidelberg, Heidelberg, Germany.
Mikalauskiene
Laura
L
Bruns
Helge
H
Nickkholgh
Arash
A
Hoffmann
Katrin
K
Longerich
Thomas
T
Strupas
Kestutis
K
Büchler
Markus W
MW
Schemmer
Peter
P
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D019587:Dietary Supplements; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D005998:Glycine / Q000008:administration & dosage*; D007150:Immunohistochemistry; D000077146:Irinotecan; D007728:Kupffer Cells / Q000473:pathology; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008833:Microcirculation; D020360:Neoadjuvant Therapy / Q000009:adverse effects; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D010587:Phagocytosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D000637:Transaminases / Q000032:analysis
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000637:Transaminases; D002955:Leucovorin; D005998:Glycine; D005472:Fluorouracil; D002166:Camptothecin