Chronic Intermittent Hypoxia Causes Lipid Peroxidation and Altered Phase 1 Drug Metabolizing Enzymes in the Neonatal Rat Liver

Abstract

Critically ill preterm neonates requiring oxygen therapy often experience frequent apneas with intermittent hypoxia (IH). IH-induced oxidative stress causes lipid peroxidation, which targets the liver and contributes to toxic drug reactions. We tested the hypothesis that incremental IH episodes induce oxidative damage in the neonatal liver and alter the expression of genes that regulate drug metabolism. Newborn rats were exposed to increasing IH episodes (12% O2) during hyperoxia (50% O2), or placed in room air (RA) until postnatal day 21 (P21) for recovery from IH (IHR). RA littermates served as controls, and pups exposed to 50% O2 served as hyperoxia controls. Hepatic histopathology, biomarkers of oxidative stress and oxidative DNA damage, antioxidants, and expression of genes that regulate drug metabolism were assessed. Oxidative stress and DNA damage, evidenced by 8-isoprostaglandin F2α (8-isoPGF2α) and 8-hydroxy-2′-deoxyguanosine (8-OH-dG), respectively, increased as a function of IH episodes, and was associated with decreased superoxide dismutase (SOD) and increased catalase activities. Pathological changes including cellular swelling, steatosis, necrosis, and focal sinusoid congestion were seen in IH, but not in IHR. Similarly, IH was associated with upregulation of several genes involved in DNA repair, which were downregulated during IHR. Of the genes involved in drug metabolism, aldehyde dehydrogenases (involved in lipid peroxidation) and cytochrome P450 (CYP) genes of the 2C family (involved in oxidative stress) were robustly upregulated both in IH and in IHR. Hepatic oxidative stress and lipid peroxidation occurring in response to chronic IH have implications for preterm infants, and may explain, in part, the pharmacokinetic variations and drug toxicities in this vulnerable population.

Co-Enzyme Q10 and n-3 Polyunsaturated Fatty Acid Supplementation Reverse Intermittent Hypoxia-Induced Growth Restriction and Improved Antioxidant Profiles in Neonatal Rats

“…Our hypothesis was tested with the following objectives: (1) to examine and compare the effects of CoQ10 and n -3 PUFA supplementation during IH exposure on somatic growth accretion in neonatal rats; (2) to establish whether CoQ10 and/or n -3 PUFAs influence factors that regulate postnatal growth; and (3) to determine whether CoQ10 and/or n -3 PUFAs improve the antioxidant profiles of neonatal rats exposed to IH. These studies of different treatment strategies and IH paradigms, extend our previous work [ 6 , 12 , 13 , 15 , 23 , 47 ], and therefore describe a more complete picture of the heterogeneity in responses during IH that are clinically relevant since IH events experienced by ELBW/ELGA neonates can resolve in normoxia or hyperoxia.…”

“…The IH profiles consisted of: (1) an initial exposure of hyperoxia (50% O 2 ) for 30 min followed by three brief, 1-min, clustered hypoxic events (12% O 2 ), with a 10-min re-oxygenation in 50% O 2 between each hypoxic event. Recovery from IH (IHR) occurred in 50% O 2 following each clustered IH event for 2.5 h for a total of 8 clustering IH episodes per day for 14 days, as previously described [ 6 , 12 , 13 , 15 , 47 ]; or (2) an initial exposure of normoxia (21% O 2 ) for 30 min followed by three brief, 1-min, clustered hypoxic events (12% O 2 ), with a 10-min re-oxygenation in 21% O 2 between each hypoxic event. Recovery occurred in normoxia following each clustered IH event for 2.5 h for a total of 8 clustering IH episodes per day for 14 days.…”

“…IH-induced ROS are toxic and damaging to lipid cell membranes leading to lipid peroxidation [ 8 ]. In addition, ROS destroy cell enzyme mechanisms and DNA; it plays a major role in inflammatory processes, and impairment of multiple neonatal systems, including the brain [ 9 ], eyes [ 6 , 10 ], heart [ 11 ] lungs [ 5 , 12 ], liver [ 13 , 14 ], and kidneys [ 15 , 16 ]. ROS are implicated in the pathogenesis, progression, and severity of a variety of neonatal morbidities, such as retinopathy of prematurity, chronic lung disease, patent ductus arteriosus, apnea of prematurity/bradycardia, sepsis, intraventricular hemorrhage [ 17 , 18 , 19 , 20 ].…”

Combination Antioxidant/NSAID Therapies and Oral/Topical Ocular Delivery Modes for Prevention of Oxygen-Induced Retinopathy in a Rat Model

“…However, one of the most disturbing findings was the deleterious effect of IH on nGSH growth promotion. While this phenomenon has not been appreciably investigated, particularly in ELGANs who experience frequent IH and apneic events during the first few weeks of life, there are a few studies that have shown that IH impairs drug metabolism [ 64 , 65 , 66 ], suggesting reduced efficacy. This may have a significant impact on pharmacokinetics in ELGANs who are exposed to numerous drugs due to multiple morbidities.…”

Intermittent hypoxia suppression of growth hormone and insulin-like growth factor-I in the neonatal rat liver

“…Each pup was weighed and measured for linear growth (crown to rump length in centimeters). A total of 31 groups of 18 rat pups (9 males and 9 females) were studied according to the experimental design previously published [46–49]. The groups are described as follows: 1) Groups 1 to 6 were exposed to 2, 4, 6, 8, 10 or 12 IH cycling episodes from P0 to P7; 2) Groups 7 to 12 were exposed to 2, 4, 6, 8, 10 or 12 IH cycling episodes from P0 to P14; 3) Groups 13 to 18 were exposed to 2, 4, 6, 8, 10 or 12 IH cycling episodes from P0 to P7, followed by re-oxygenation in room air (RA) for 14 days from P7 to P21; 4) Groups 18 to 24 were exposed to 2, 4, 6, 8, 10 or 12 IH cycling episodes from P0 to P14, followed by re-oxygenation in RA for 7 days from P14 to P21; 5) Groups 25 to 28 were exposed to hyperoxia (Hx) consisting of 50% O 2 only for 7 days, 14 days, 7 days with 14 days of re-oxygenation in RA, or 14 days with 7 days of re-oxygenation in RA.…”