LCT, pyrethroid insecticide type II, is extensively utilized in public health and agriculture controlling pests . Its widespread use consequently leads to the exposure of its possible toxic effects either directly by exposure of field applicators, manufacturing workers, and the ecosystem or indirectly by consumption of vegetables, fruits , and meat or milk of animals that exposed to LCT [40, 41].
Liver is the principal site of pyrethroid metabolism where large quantities of their metabolites are accumulated . LCT metabolism occur rapidly in liver by hydrolytic cleavage of ester and oxidative pathways via CYP450 enzymes leading to ROS  causing damage of various components of cell membranes  resulting in alterations the antioxidant status, ROS, the antioxidant enzymes, LPO , and apoptosis that represent major contributors in hepatic damage. Thus, our study estimates the potential ameliorative effect of G in rat model of LCT-induced hepatotoxicity.
In the current study, terminal body weight and relative weight of liver of LCT-intoxicated rats were reduced that run in a good agreement with previous studies [14, 45,46,47,48].
Elhalwagy et al.  demonstrated that decreasing body weight and organs relative weight is one of the chronic effects of pyrethroids toxicity. In LCT-intoxicated rats, the observed decrease may be directly linked to hypophagia or emaciation because of LCT’s direct cytotoxicity .
Both in vivo and in vitro researches reported that G decrease biological, physical, and chemical stress and maintain general vitality . In our study, treatment of rats with LCT in concomitant with G 100 or 200 mg/kg b. wt./day increased terminal body weight, relative weight of liver, as compared to LCT-intoxicated ones matching with previous studies. Qadir et al.  demonstrated that G protects mice from body weight loss and improved kidney weight induced by gentamicin toxicity.
The current study indicated that LCT-intoxication caused extensive damage in the liver of rats that was confirmed by the histopathological and ultrastructural alterations and reflected by marked elevations of AST, ALT, and ALP activities, which are the circulating markers of hepatocytes injury.
Increased serum ALT and AST activities reflect LCT-induced hepatotoxicity, causing these enzymes to leak into blood [51, 52]. These observations matched with earlier finding of LCT toxicity in rats [1, 8, 15, 47, 53, 54]. ALT activity reflects general hepatic damage and AST activity indicates mitochondrial damage; elevated levels of ALP in blood are regarded as an indicator of hepatic necrosis and cholestasis [55, 56]. The elevated levels of serum ALT and AST have been related to liver structural integrity damage [57, 58], as they are cytoplasmic enzymes and are released into blood after hepatic injury . Releasing of metabolically toxic intermediates able to cause hepatocellular injury which happen during LCT metabolism in the liver, leading to these enzymes leakage to blood . The increase or decrease of enzyme activity depends on the intensity of cellular damage. In the present study, the increased LPO products (MDA) level in liver of LCT-intoxicated rats and the elevation AST and ALT activities in serum proposed that LCT induced hepatocellular injury and this injury happened likely by ROS. That suggests that an elevation in the activity ALT in parallel with reduction in free radical scavenging enzymes activities [1, 14, 53] could be representative of LCT-induced hepatic pathological alterations.
ALP is excreted through the liver by bile. Cholestasis, due to bile duct obstruction, cause enzymes to regurge that raise its blood level due to its back pressure that lead it to leach into blood. Biliary impairment could be explained similarly. Elevated ALT, AST, and LDH activities concomitant with an increase in level of bilirubin in serum indicate cholestasis that lead to elevated serum ALP level . Destruction of hepatic tissue (necrosis) also may have accounted for elevation in ALP level in serum. Because of pesticide toxicity, parenchymal cells of liver are deteriorated and necrosed, thus ALT, AST, and ALP release into the circulating blood stream, resulting in increased levels [62, 63]. Bhushan et al.  reported that an increase of serum ALP could be linked initially to some hepatic patho-physiological alterations as a result of pesticide toxicity, likely because of hepatocytes membrane permeability damage, so enzymes leak to blood stream.
In the present study, treatment of LCT-intoxicated rats with either 100 or 200 mg G/kg b. wt./day produced a profound improvement of the altered ALT, AST, and ALP activities in serum. G reduced the elevated of AST, ALT, and ALP activities in serum of fipronil intoxicated rats and 100 mg G/kg b. wt./day  or chlorpyrifos and profenofos and 200 mg G/kg b. wt./day , conforming the protective effect of G against liver damage.
Oxidative stress has been described as losing balance between antioxidants and oxidants due to general elevation in ROS cellular levels . It is known as a risk factors for the development of various diseases .
ROS are compounds that contain oxygen generated via general metabolic pathways, which are reported to cause oxidative damage to lipids, proteins, and nucleic acid .
Pesticides cause oxidative stress that leads to free radicals formation, changes in the levels of antioxidants, and LPO . LPO is widely used as an oxidative stress marker. MDA is a main oxidation product of peroxidized polyunsaturated fatty acids and elevated MDA level is a LPO’s accurate determinant . In the current study, LCT produced a significant increase in the level of MDA in liver tissues. The increase in extent of LPO likely because of free radicals production as a result of LCT exposure. These observations are matched with earlier finding of LCT-hepatotoxicity [1, 8, 14, 53, 54, 71].
LPO results from lipid reaction with free radicals and this is regarded as a significant aspect of cellular damage caused by attacks of free radical . This indicates that elevated LPO could be among the molecular mechanisms implicated in the toxicity caused by LCT in rats.
Even so, in case of heavily established oxidative stress, the defense capacities against ROS becomes insufficient; in turn, ROS also affect the antioxidant defense mechanisms, decreases the intracellular thiol level, the antioxidant enzymes activities is altered, and MDA is increased . Indirectly, these indicate an elevated generation of oxygen free radicals. Highly reactive oxygen metabolites, especially •OH, produce MDA by acting on unsaturated fatty acids of phospholipid components of membranes .
CAT and SOD play a major role in quenching of ROS. SOD act as catalyst for breaking down of O2•¯to H2O2, while CAT act as catalyst for decomposition of H2O2 into H2O and O2 to inhibit oxidative stress and to maintain cell homeostasis. In the current study, CAT and SOD activities were significantly reduced in liver of LCT-treated rats that run in parallel with the results of [8, 15, 25, 74, 75]. Both CAT and SOD act with each other for ROS elimination, and minor deviations in physiological levels could have a dramatic effect on cellular proteins, nucleic acid, and lipids resistance to oxidative stress . In the LCT group, low CAT and SOD levels may be attributed to these enzymes consumption due to elevated oxidative stress in liver.
Thiols are a sulphydryl group containing organic compounds. Among all the body’s antioxidants, thiols represent the main part of the total body antioxidants and they have an important role in defense against ROS. Thiols comprised of both extracellular and intracellular thiols either in the free form as reduced or oxidized glutathione, and protein-bound thiols . In the current study, T. thiol is decreased in liver of LCT-intoxicated rats matching those of previous study .
Antioxidants are the compounds which react with ROS for slowing their action and for neutralizing them, thus reducing oxidative stress and protecting us from ailments . Normally, our cells are able to inhibit ailments caused by free radicals by producing its endogenous antioxidants or via taking them from food . Some synthetic antioxidants were used for preventing oxidative stress may cause side effects . Thus, the regular consumption of natural antioxidant in diets is regarded very important to ban a broad spectrum of ailments, such as allergies, some types of cancer, hepatic and cardiovascular ailments, and inflammation that include free radical-mediated damage in pathologically generating processes .
The antioxidant properties of G are well documented. G exhibits antioxidant activity by improving the expressions of antioxidant enzyme genes that help to scavenge ROS. G intake stimulates both antioxidant enzyme activity and scavenging of free radicals . G improved the antioxidant defense mechanism by increasing self-antioxidant enzyme activities (SOD, CAT, GPx, GR, GSH) and heme oxygenase-1 in the aged-rat liver [19, 21] and inhibition of lipid peroxidation [23, 28]. However, its effect on inhibition of hepatotoxins-induced liver damages in rats cannot be neglected [22, 82].
In the present study, co-administration of G with LCT caused a significant decrease in the mean value of MDA and a significant increase in the mean values of antioxidant enzymes (SOD and CAT) activities and T. thiol in liver as compared with LCT-treated group. Similarly, Al-Harbi et al.  demonstrated that G, due to its antioxidant properties, reduced MDA level, and elevated CAT and SOD activities in fipronil treated rats. Also, Diab et al.  reported that G administration decreased MDA levels, and increased SOD, CAT activities in chlorpyrifos and profenofos-treated animals.
In conjunction with impaired antioxidant defense system, the present study exhibited significant elevation in mRNA and protein expression levels of hepatic p53 concomitant with decrease in mRNA and protein expression levels of Bcl2 in LCT-treated rats in comparison with control group. Apoptosis, the process of programmed cell death, is necessary for management of numbers of cells by elimination of damaged cells for better functioning of the body. But excessive tissue damage is caused by an uncontrolled and unconditioned apoptosis. Exposure of rats to LCT results in the generation of ROS, DNA fragmentation, and apoptosis [53, 66]. A possible mechanism of LCT-caused apoptosis was demonstrated to be related with activation of a transcription factor, nuclear factor-kappa B (NF-κB) which is a critical activator of genes involved in immunity, inflammation, and apoptosis . However our study did not estimate NF-κB; Martínez et al.  reported an elevation of mRNA expression level of NF-κB and interleukin (IL-1β) in hepatic tissues secondary to LCT-induced oxidative stress. Activation of NF-κB causes reduction in proliferation of cells and elevation in apoptosis by ROS-caused DNA damage and p53 activation. Activated p53 due to LCT oral exposure also activates the intrinsic mitochondrial apoptotic pathways responding to DNA damage by stimulating the expression of pro-apoptotic proteins (Bax, Casp-3), downregulates Bcl-2 expression, and shifts the balance toward pro-apoptotic effects . Co-treatments with G significantly decrease mRNA and protein expression of p53 and increase mRNA and protein expression of Bcl-2 in hepatic tissue in comparison with LCT group. Thus, it is logical to believe that an enhanced apoptotic rate in co-treated groups can be ascribed to antioxidant properties of G and the subsequent ROS scavenging, suppression of NF-κB activation, and cytokines release. G decreased the gene expression of the pro-apoptotic proteins p53 and caspase-3, while elevated expression of the anti-apoptotic Bcl2 in neuroblastoma cells suggesting the protective effects of G against the cell death in oxidative stressed brain cells . Also, G suppresses TNF-α/IFN-c-induced thymus- and activation-regulated chemokine (TARC) expression through NF-κB-dependent signaling in HaCaT cells. G improved 2,4-dinitrochlorobenzene (DNCB)-induced dermatitis severity, serum levels of IgE and TARC, and mRNA express ion of TARC, TNF-α, IFN-c, IL-4, IL-5, and IL-13 in mice. G inhibited TNF-α /IFN-c-induced NF-κB activation .
Another molecular mechanism study found that G suppresses nuclear factor-kappa B (NF-κB) [85, 86].
The present histopathological observations of liver sections of LCT-intoxicated rats showed mononuclear leukocytic infiltration, portal vein congestion with thickening in wall, and bile duct proliferation was also observed. In addition to hyperemic sinusoids, fatty changes, and edema. Degenerative changes were seen in the hepatocytes in the form of vacuolar degeneration, hypereosinophilic cytoplasm, pyknosis, and karyolysis, in agreement with previous studies [15, 87, 88]. Also, Abdul Basir et al.  reported that LCT-intoxicated rabbits exhibited hemorrhages in sinusoidal spaces hyperplasia of bile duct, karyolysis, and vacuolation. LCT-intoxicated mice also showed hepatocyte degeneration, vascular degeneration, mononuclear leukocytic infiltration, and portal vein appeared dilated and congested [90, 91].
In addition to similar histopathological observations, it has been reported by Mossa et al.  and Abdul-hamid et al.  on the effect of cypermitherin (CYP), type II pyrithroids, on liver tissue. These histopathological changes in the hepatocytes due to CYP’s inhibitory action on total adenine triphosphate (ATP) activity in the liver, that can disturb active transport of Ca2+, K+, and Na+ ions, inducing hepatocytes damage .
Matching with histopathological findings, our ultrastructural study showed that LCT-intoxicated rats exhibited damaged bile canaliculi with destructed microvilli, Kupffer cell showed shrinked nucleus, hepatocytes with vacuolated mitochondria, cytoplasmic vacuolations, fat droplets, and collagen fibers in parallel line with similar previous studies. Marked ultrastructural alterations were exhibited in previous studies of CYP intoxicated rats. In hepatocytes, mitochondria looked swollen, vacuolated with destructed cristae, cytoplasmic vacuolations, complete lysis of nucleus and dilated bile duct with destruction in microvilli, fat droplets, and cytoplasmic vacuoles were also observed. Moreover, Kupffer cell appeared with elongated nucleus, endocytic vesicles, and noticeable elevation in number of lysosomes [93, 95, 96].
Concerning the hepatocytes, fatty changes in the form of fat droplets in the cytoplasm can be rationalized by the high levels of LPO that resulted from LCT-induced oxidative damage, and its effect on membrane phospholipids.
After several types of hepatocellular damage, healing normally occur by regeneration of parenchymal cells and substitution of stromal elements coordinately that preserves accurately the lobular architecture of hepatic tissue. While, in some cases for unknown causes, abnormal quantities of collagen accumulate impairing the normal relationships between the parenchymal cells and its blood supply. That is known as liver fibrosis or cirrhosis, which can impair hepatic function or even death  that matching with the current ultrastructural observation of collagen accumulation in hepatic tissue of LCT-intoxicated rats.
In the current study, treatment of LCT-intoxicated rats with G 100 mg/kg b.wt./day and 200 mg/kg b. wt./day plus LCT protected liver of LCT hepatic toxicity and maintain approximately the normal histological structure matching with similar previous studies. El-Bialy et al.  demonstrated that G 200 mg/kg. b. wt./day ameliorates LCT and acetamiprid pesticides mixture for hepatotoxicity in rats and restore normal hepatic architecture.